Therapeutic compounds for inhibiting interleukin-12 signaling and methods for using same

ABSTRACT

Novel heterocyclic compounds having a six membered ring structure fused to a five membered ring structure are found to be useful for the treatment and prevention of symptoms or manifestations associated with disorders affected by lnterleukin-12 (“IL-12”) intracellular signaling, such as, for example, Th1 cell-mediated disorders. The therapeutic compounds, pharmaceutically acceptable derivatives (e.g., resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, have the following general formula:  
                 
 
     Each X, Y and Z are independently selected from a member of the group consisting of C(R 3 ), N, N(R 3 ) and S. Each R 1 , R 2  and R 3  is substituted or unsubstituted and is independently selected from a member of the group consisting of hydrogen, halo, oxo, C (1-20) alkyl, C (1-20) hydroxyalkyl, C (1-20) thioalkyl, C (1-20) alkylamino, C (1-20) alkylaminoalkyl, C (1-20) aminoalkyl, C (1-20) aminoalkoxyalkenyl, C (1-20) aminoalkoxyalkynyl, C (1-20) diaminoalkyl, C (1-20) triaminoalkyl, C (1-20) tetraaminoalkyl, C (5-15) aminotrialkoxyamino, C (1-20) alkylamido, C (1-20) alkylamidoalkyl, C (1-20) amidoalkyl, C (1-20) acetamidoalkyl, C (1-20) alkenyl, C (1-20) alkynyl, C (3-8) alkoxyl, C (1-11) alkoxyalkyl, and C (1-20) dialkoxyalkyl.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a (1) continuation-in-part of U.S.application Ser. No. 09/288,556, which was filed Apr. 9, 1999, which inturn is a continuation-in-part of U.S. application Ser. No. 09/008,020,which was filed Jan. 16, 1998; (2) continuation-in-part of allowed U.S.application Ser. No. 08/486,264, which was filed Jun. 7, 1995, which inturn is a continuation-in-part of abandoned U.S. application Ser. No.08/217,051, which was filed Mar. 24, 1994; and (3) continuation-in-partof allowed U.S. application Ser. No. 08/483,871, which was filed Jun. 7,1995, which in turn is a continuation-in-part of abandoned U.S.application Ser. No. 08/199,368, which was filed Feb. 18, 1994. Theentire disclosures of the above-identified patent applications areincorporated herein by reference and the benefit of each is herebyclaimed.

FIELD OF THE INVENTION

The present invention generally relates to novel therapeutic compounds,pharmaceutical compositions containing such compounds, methods forpreparing such compounds and methods for using these compounds, alone orin combination with other therapeutic agents, for the treatment andprevention of symptoms or manifestations (e.g., inflammation) associatedwith disorders affected by Interleukin-12 (“IL-12”) intracellularsignaling, such as, for example, Th1 cell-mediated disorders.

BACKGROUND OF THE INVENTION

Inflammatory responses are a component of the pathogenesis of manyvertebrate disorders/diseases, including those in humans. In itsbroadest meaning, the term “inflammation” denotes local as well assystemic responses. Increased blood flow, vasodilation, fluidtransudation from the vessels, infiltration of the tissues by leukocytesand, in some severe cases, intravascular thrombosis, damage to the bloodvessels and extravasation of blood characterize local inflammation. Thesystemic inflammatory response, also denoted as an acute phase response,is characterized by various reactions including, for example, fever,leukocytosis and release of acute phase reactants into the serum. Insevere cases, shock and death may occur. See Heremans et al., LymphokineResearch 8(3): 329-333 (1989). Diseases involving inflammation areparticularly harmful when they afflict the respiratory system, resultingin obstructed breathing, hypoxemia, hypercapnia and lung tissue damage.Obstructive diseases of the airways are characterized by airflowlimitation (i.e., airflow obstruction or narrowing) due to constrictionof airway smooth muscle, edema and hypersecretion of mucous leading toincreased work in breathing, dyspnea, hypoxemia and hypercapnia. Whilethe mechanical properties of the lungs during obstructed breathing areshared between different types of obstructive airway diseases, thepathophysiology can differ.

The inflammatory response is believed to be controlled by a variety ofcellular events characterized by the influx of certain cell types andmediators, the presence of which can lead to tissue damage and sometimesdeath. For example, cytokines are primary factors in the biochemicalcascade of events that regulate inflammatory responses. Some cytokinesinduce or release other known mediators of inflammation. These systemsare controlled by related feedback mechanisms. Thus, it is believed thatinflammatory responses are not a result of a single cytokine beingreleased in large quantities, but rather to a set of cytokinescollectively acting via a network of intercellular signals to incite theinflammatory response.

One particular cytokine, IL-12, also referred to as natural killer cellstimulatory factor (“NKSF”) or cytotoxic lymphocyte maturation factor(“CLMF”), is a potent immunoregulatory molecule that plays a role in awide range of diseases. In particular, IL-12 is a heterodimeric cytokinethat is produced by phagocytic cells, e.g., monocytes/macrophages,B-cells and other antigen-presenting cells (“APC”) and is believed toact as a proinflammatory cytokine. IL-12 is believed to play a specificrole in diseases exhibiting an inflammatory component, namely, diseasesthat exhibit cell-mediated inflammatory responses, such as, multiplesclerosis, diabetes, chronic inflammatory bowel disease, etc.

IL-12 affects both natural killer cells (“NK cells”) and T-lymphocytes(“T cells”), and stimulates IFNγ production by both of these cell types.For example, in NK cells, IL-12 stimulates: NK cell proliferation,membrane surface antigen up-regulation, LAK cell generation and NK cellactivity elevation; induces IFN-γ and TNF-α production and the growthand expansion of either resting or activated NK cells; and increasessoluble p55 and soluble p75 TNF receptor production and NK cellcytotoxicity. See R&D Systems Catalog, pp. 67-69 (1995). T cellsrecognize antigens via interaction of a heterodimeric (alpha/beta, orgamma/delta) receptor with short peptide antigenic determinants that areassociated with major histocompatibility complex (“MHC”) molecules. Tcells can be divided broadly into two functional categories by thepresence of two mutually exclusive antigens on their cell surface, CD4(helper) and CD8 (cytotoxic). The CD4 and CD8 antigens regulate T cellinteraction with MHC and their mutually exclusive expression derivesfrom their strict specificity for MHC. Class II MHC-restricted T cellsare primarily CD4+ and class I MHC-restricted T cells are CD8+. The Tcells further differentiate into helper, cytotoxic and suppressor cells.

As mentioned above, IL-12 also affects T cells, including stimulation ofT cell IFN-γ production in response to antigen. While CD8+ T cells areassociated with cytotoxicity functions, CD4+ T cells are associated withhelper function and secrete various cytokines that regulate and modulateimmune responses. CD4+ T cells can be further subdivided into T helper 1(Th1) and T helper 2 (Th2) subsets, according to the profile ofcytokines they secrete. Therefore, Th1 cells produce predominantlyinflammatory cytokines, including IL-2, TNF-α and IFN-γ, while Th2 cellsproduce anti-inflammatory cytokines such as IL4, IL-5, IL-10, and IL-13that are linked to B cell growth and differentiation.

The Th1 and Th2 CD4+ T cell subsets are derived from a common progenitorcell, termed Th0 cells. During an initial encounter with an antigen, thedifferentiation into Th1 and Th2 is controlled by the opposing actionsof two key cytokines, namely IL-12 and IL4, which induce thedifferentiation of Th0 into Th1 and Th2, respectively. The developmentof Th1 and Th2 cells is primarily influenced by the cytokine milieuduring the initial phase of the immune response, in which IL-12 and IL4,respectively, play decisive roles. The cytokines produced by eachTh-cell phenotype are inhibitory for the opposing phenotype. Forexample, Th1 cytokines enhance cell-mediated immunities and inhibithumoral immunity. Th2 cytokines enhance humoral immunity and inhibitcell-mediated immunities. Trembleau et. al., See Immunology Today 16(8):383-386 (1995).

Furthermore, CD4+ Th1 cells play a role in the pathogenesis ofimmunological disorders. These cells primarily secrete cytokinesassociated with inflammation such as IFN-γ, TNF-α, TNF-β and IL-2. IFN-γis an important component of the inflammatory response and resultantpathology of those diseases exhibiting an inflammatory response.Heremans, et al. In addition to its role in inflammatory response, IFN-γalso contributes to phagocytic cell activation (i.e., macrophageactivation), and up-regulation of MHC expression on the surface ofantigen-presenting cells (“APC”) and other cells. Further, this cytokineis implicated generally in inflammatory immune responses, and inautoimmune diseases, such as multiple sclerosis (“MS”), specifically.See Owens et al., Neurologic Clinics, 13(1):51-73 (1995). Furthermore,steroid treatment broadly attenuates cytokine production, but it cannotmodulate it selectively, e.g., just the Th0, the Th1 or the Th2pathways.

IL-12 plays a role in the induction of Th1-cell-mediated autoimmunity.Recent evidence points to a critical role for IL-12 in the pathogenesisof rodent models of Th1-mediated autoimmune diseases such as type-1diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory boweldisease, and acute graft-versus-host disease. Thus, Th1 cells arebelieved to be involved in the induction of experimental autoimmunediseases, as demonstrated in adoptive transfer experiments demonstratingthe CD4+ cells producing Th1-type lymphokines can transfer disease, asshown in models of experimental autoimmune disease, such as experimentalallergic encephalomyelitis (“EAE”) (also known as experimental allergicencephalitis) and insulin-dependent diabetes mellitus (“IDDM”). SeeTrinchieri, Annu. Rev. Immunol 13(1):251-276 (1995). For instance, EAEis an inflammatory T cell mediated, paralytic, demyelinating, autoimmunedisease that can be induced in a number of rodents as well as primates.Owens et al. One of the ways that EAE can be induced is by immunizationof animals with myelin basic protein (“MBP”). Likewise, administrationof IL-12 induces rapid onset of IDDM in 100% of NOD female mice.Trinchieri. Thus, one goal of immunotherapy research and developmentefforts has been to limit inflammatory response while leaving thespecificity of the immune system, deemed necessary for host protection,in tact.

For example, steroid therapy is the most common treatment for one suchIL-12 mediated disease, MS, particularly, corticosteroids. This suggeststhat steroids alter the trafficking of cells into the brain or reducethe secretion of cytokines by inflammatory cells in areas ofinflammation. Although their effect in reversing some of the acutesymptoms of autoimmune disease, such as MS, are well known, their sideeffects have precluded long-term use.

Other treatments that target immune system components include lymphocytecytotoxic drugs such as cyclophosphamide and azathioprine. These drugsact like “sledgehammers” in that they suppress the entire immune systemand raise problems that attend broad-spectrum immunosuppressiontherapies. The same problems also are likely with newer therapies suchas cyclosporine, anti-CD4 monoclonal antibodies, and others. Othertreatments for IL-12 mediated diseases, including MS, can involve theadministration of anti-IL-12 antagonists such as antibodies. Anti-IL-12antibodies have been shown to inhibit the development of IDDM and EAE.See Trinichieri. However, antibody based immunotherapy may result inimmune complex formation and deposition, thus leading toglomerulonephritis, vasculitis and arthritis.

Moreover, symptomatic treatment with beta-agonists, anticholinergicagents and methyl xanthines have been clinically beneficial for therelief of discomfort but fail to stop the underlying inflammatoryprocesses that cause the disease. The frequently used systemicglucocorticosteroids have numerous side effects, including, but notlimited to, weight gain, diabetes, hypertension, osteoporosis,cataracts, atherosclerosis, increased susceptibility to infection,increased lipids and cholesterol, and easy bruising. Aerosolizedglucocorticosteroids have fewer side effects but can be less potent andhave side effects, such as thrush.

The use of anti-inflammatory and symptomatic relief reagents is aserious problem because of their side effects or their failure to attackthe underlying cause of an inflammatory response. Otheranti-inflammatory agents, such as cromolyn and nedocromil are much lesspotent and have fewer side effects. Anti-inflammatory agents that areprimarily used as immunosuppressive agents and anti-cancer agents (i.e.,cytoxan, methotrexate and Immuran) have also been used to treatinflammation. These agents, however, have serious side effect potential,including, but not limited to, increased susceptibility to infection,liver toxicity, drug-induced lung disease, and bone marrow suppression.Thus, such drugs have found limited clinical use, for example, in thetreatment of most airway hyperresponsiveness lung diseases.

Accordingly, there remains a need for novel therapeutic compounds andmethods that inhibit the deleterious effects of inflammatory responsesmediated by specific cytokines, such as IL-12, without adverselyaffecting the other components of the immune system that are deemednecessary for protecting the host and without the attendantdisadvantages of conventionally available compounds and methods.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel therapeuticcompounds, including pharmaceutical compositions thereof and methodsuseful for inhibiting IL-12 signaling in a mammal having, for example,an inflammatory response.

It is another object of the present invention to provide noveltherapeutic compounds, pharmaceutical compositions thereof and methodsthat are capable of limiting the inflammatory response of a subjectwithout adversely affecting the specificity of the immune system deemednecessary for protecting the subject.

The above and other objects are accomplished by a compound,pharmaceutically acceptable derivatives (e.g., racemic mixtures,resolved enantiomers, diastereomers, tautomers, salts and solvatesthereof or prodrugs thereof, having the following Formula

wherein: the dashed lines, i.e.,“— - — - — -”, in Formula I representeither a single or double bond;

X, Y and Z are independently selected from a member of the groupconsisting of C(R₃), N, N(R₃) and S;

R₁ is selected from a member of the group consisting of hydrogen,methyl, substituted alkyl (as defined herein, which includes withoutlimitation substituted C₍₅₋₉₎alkyl), C₍₅₋₉₎alkenyl, C₍₅₋₉₎alkynyl,C₍₅₋₉₎hydroxyalkyl, C₍₃₋₈₎alkoxyl, C₍₅₋₉₎alkoxyalkyl; and

R₂ and R₃ are independently selected from a member of the groupconsisting of hydrogen, halo, oxo (keto), C₍₁₋₂₀₎alkyl,C₍₁₋₂₀₎hydroxyalkyl, C₍₁₋₂₀₎thioalkyl, C₍₁₋₂₀₎alkylamino,C₍₁₋₂₀₎alkylaminoalkyl, C₍₁₋₂₀₎aminoalkyl, C₍₁₋₂₀₎aminoalkoxyalkenyl,C₍₁₋₂₀₎aminoalkoxyalkynyl, C₍₁₋₂₀₎diaminoalkyl, C₍₁₋₂₀₎triaminoalkyl,C₍₁₋₂₀₎tetraaminoalkyl, C₍₅₋₁₅₎aminotrialkoxyamino, C₍₁₋₂₀₎alkylamido,C₍₁₋₂₀₎alkylamidoalkyl, C₍₁₋₂₀₎amidoalkyl, C₍₁₋₂₀₎acetamidoalkyl,C₍₁₋₂₀₎alkenyl, C₍₁₋₂₀₎alkynyl, C₍₃₋₈₎alkoxyl, C₍₁₋₁₁₎alkoxyalkyl, andC₍₁₋₂₀₎dialkoxyalkyl.

R₁ is optionally substituted with a member of the group consisting ofN—OH, acylamino, cyano (e.g., NC—), cyanamido (e.g., NCNH—), cyanato(e.g., NCO—), sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno,sulfanilyl, sulfamyl, sulfamino, and phosphino, phosphinyl, phospho,phosphono and —NR^(a)R^(b), wherein each of R^(a) and R^(b) may be thesame or different and each is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic group.

Each R₂ and R₃ is optionally substituted with one or more members of thegroup consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl,biotinyl, phenyl, naphthyl, amino group (e.g., —NH₂), amido group (e.g.,—C(═O)N—), carbamoyl group (e.g., H₂NCO—), cyano (e.g., NC—), cyanamido(e.g., NCNH—), cyanato (e.g., NCO—), sulfo, sulfonyl, sulfinyl,sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino,phosphino, phosphinyl, phospho, phosphono, N—OH, —Si(CH₃)₃, C₍₁₋₃₎alkyl,C₍₁₋₃₎hydroxyalkyl, C₍₁₋₃₎thioalkyl, C₍₁₋₃₎alkylamino,benzyldihydrocinnamoyl group, benzoyidihydrocinnamido group,heterocyclic group and carbocyclic group.

The heterocyclic group or carbocyclic group is optionally substitutedwith one or more members of the group consisting of halo, hydroxyl,nitro (e.g., —NO₂), SO₂NH₂, C₍₁₋₆₎alkyl, C₍₁₋₆₎haloalkyl, C₍₁₋₈₎alkoxyl,C₍₁₋₁₁₎alkoxyalkyl, C₍₁₋₆₎alkylamino, and C₍₁₋₆₎aminoalkyl.

Preferably, both X and Y are not N(R₃) when Z is C(R₃) and R₃ is H orC₍₁₋₃₎alkyl.

More preferably, R₁ is not an ω-1 secondary alcohol substitutedC₍₅₋₈₎alkyl when both X and Y are N(R₃), Z is C(R₃) and R₃ is H orC₍₁₋₃₎alkyl.

In a further aspect, the present invention is directed to a method forinhibiting a cellular process or activity mediated by IL-12, the methodcomprising:

(a) contacting IL-12 responsive cells with a compound of the presentinvention, as described herein; and

(b) determining that the cellular process or activity mediated by IL-12is inhibited.

In a still further aspect, the present invention is directed to a methodfor treating a Th1 cell-mediated inflammatory response in a mammal inneed of such treatment, the method comprising:

administering to the mammal a therapeutically effective amount of thecompound of the present invention, wherein said compound is capable ofinhibiting an IL-12 mediated cellular process or activity, therebyinhibiting the inflammatory response.

In accomplishing the above and other objects, the present inventionprovides novel therapeutic compounds and methods for affecting, interalia, the inflammatory response associated with Th1 cell-mediateddiseases, without affecting the other components of the immune systemthat are deemed necessary for host protection. The compounds and methodsof the present invention are characterized by their ability to inhibitIL-12 signaling. Without wishing to be bound by theory, it is believedthat the therapeutic compounds of the present invention short-circuitthe inflammatory cascade by inhibiting IL-12-dependent Th1 development,emphasizing the present invention's importance in disease therapy byinhibiting IL-12 signaling in the regulation of Th1-mediatedinflammatory disorders. Inhibition of IL-12 signaling decreases theproduction of IFN-γ, thus mitigating the inflammatory response indisease conditions mediated by Th1 cells. Specifically, the presentinvention may impede signaling that induces differentiation of T cellsto Th1 cells. In general, differentiated Th1 cells produce high levelsof IFN-γ, which provokes inflammation, a component of many diseaseconditions that the inventive compounds and methods target.

The present invention achieves the above and other objects by, interalia, providing novel therapeutic compounds and methods for treating orpreventing IL-12 or Th1 mediated symptoms (e.g. inflammation) ofdiseases that include, without limitation, (1) inflammatory diseases ordisorders, such as, for example, arthritis, asthma, chronic inflammatorydiseases, chronic intestinal inflammation, psoriasis, septic shock,septicemia, and adult respiratory distress syndrome; (2) autoimmunediseases or disorders, such as, for example, acute and chronicgraft-versus-host disease, autoimmune gastritis, autoimmune hemolyticanemia, autoimmune neutropenia, chronic active hepatitis, chronicthyroiditis, inflammatory bowel disease (e.g., Crohn's Disease andulcerative colitis), lupus disorders (e.g., systemic lupuserythematosus), multiple sclerosis, myasthenia gravis, rheumatoidarthritis, scleroderma, thrombocytopenia, thyroid diseases (e.g.,Graves' and Hashimoto's disease), type-1-IDDM, and uveitis; and (3)neurodegenerative diseases such as, for example, amyotrophic lateralsclerosis, Alzheimer's disease, Parkinson's disease, and primary lateralsclerosis. The compounds of the present invention may be employed in anysuitable conventional manner for the treatment of the above diseases.Such methods of treatment, their dosage levels and requirements may beselected by those of skill in the art from available methods andtechniques that are further described below, that are known in the artor that are readily determinable using routine experimentation.

The compounds of the present invention will also be useful forinhibiting IL-12 mediated signaling in other applications such as invitro systems and in vivo animal models of IL-12 mediated diseases.Accordingly, the present invention encompasses a kit comprising acompound of the present invention, as described herein, for use in suchapplications.

Additional aspects, embodiments and advantages of the present inventionwill be set forth, in part, in the description that follows, or may belearned from practicing or using the present invention. The objects andadvantages may be realized and attained by means of the features andcombinations particularly pointed out throughout this description andthe appended claims. It is to be understood that the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not to be viewed as being restrictive of theinvention as claimed.

BRIEF DESCRIPTION OF THE DRAWING

The accompanying drawing, which is incorporated in and constitutes apart of the specification, illustrates an embodiment of the presentinvention and, together with the description, serves to exemplify theprinciples of the present invention.

FIG. 1 shows the ability of(R)-3-(6-biotinylamidohexyl)-1-(5-hydroxyhexyl)-7-methylxanthine (CT12460) and(R)-3-(6-biotinylamidoethyl)-1-(5-hydroxyhexyl)-7-methylxanthine (CT13410) to interfere with IL-12 signaling in an IL-12 induced IFN-γsecretion assay.

FIG. 2 shows the inhibitory effect of(R)-1-(5-N,N-dimethylaminohexyl)-3,7-dimethylxanthine (CT11558) in anadoptive transfer experimental allergic encephalomyelitis (EAE) model.

FIG. 3 shows the inhibitory effect of(R)-1-(5-hydroxyhexyl)-3-methyl-8-(N-methyl)aminomethylxanthine(CT12441) against GVHD.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

All patents, patent applications and publications cited in thisdescription are incorporated herein by reference in their entirety. Inthe case of inconsistencies, the present disclosure, includingdefinitions, will prevail.

The present invention relates to a new class of heterocyclic compoundshaving a six membered ring structure fused to a five membered ringstructure. In particular, the present invention provides a compound,pharmaceutically acceptable derivatives (e.g., racemic mixtures,resolved enantiomers, diastereomers, tautomers, salts and solvatesthereof) or prodrugs thereof, having the following Formula I:

wherein:

the dashed lines, i.e., “— - — - — -”, in Formula I represent a singleor double bond;

X, Y and Z are independently selected from a member of the groupconsisting of C(R₃), N, N(R₃) and S;

R₁ is selected from a member of the group consisting of hydrogen,methyl, substituted alkyl (as defined herein, which includes withoutlimitation substituted C₍₅₋₉₎alkyl), C₍₅₋₉₎alkenyl, C₍₅₋₉₎alkynyl,C₍₅₋₉₎hydroxyalkyl, C₍₃₋₈₎alkoxyl, C₍₅₋₉₎alkoxyalkyl; and

R₂ and R₃ are independently selected from a member of the groupconsisting of hydrogen, halo, oxo, C₍₁₋₂₀₎alkyl, C₍₁₋₂₀₎hydroxyalkyl,C₍₁₋₂₀₎thioalkyl, C₍₁₋₂₀₎alkylamino, C₍₁₋₂₀₎alkylaminoalkyl,C₍₁₋₂₀₎aminoalkyl, C₍₁₋₂₀₎aminoalkoxyalkenyl, C₍₁₋₂₀₎aminoalkoxyalkynyl,C₍₁₋₂₀₎diaminoalkyl, C₍₁₋₂₀₎triaminoalkyl, C₍₁₋₂₀₎tetraaminoalkyl,C₍₅₋₁₅₎aminotrialkoxyamino, C₍₁₋₂₀₎alkylamido, C₍₁₋₂₀₎alkylamidoalkyl,C₍₁₋₂₀₎amidoalkyl, C₍₁₋₂₀₎acetamidoalkyl, C₍₁₋₂₀₎alkenyl,C₍₁₋₂₀₎alkynyl, C₍₃₋₈₎alkoxyl, C₍₁₋₁₁₎alkoxyalkyl, andC₍₁₋₂₀₎dialkoxyalkyl.

R₁ is optionally substituted with a member selected from the groupconsisting of N—OH, acylamino, cyano (e.g., NC—), cyanamido (e.g.,NCNH—), cyanato (e.g., NCO—), sulfo, sulfonyl, sulfinyl, sulfhydryl(mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino,phosphinyl, phospho, phosphono and —NR^(a)R^(b), wherein each of R^(a)and R^(b) may be the same or different and each is independentlyselected from the group consisting of hydrogen, optionally substitutedalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl andheterocyclic group.

Each R₂ and R₃ is optionally substituted with one or more members of thegroup consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl,biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group,cyano (e.g., NC—), cyanamido (e.g., NCNH—), cyanato (e.g., NCO—), sulfo,sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl,sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono, N—OH,—Si(CH₃)₃ (a.k.a. SiMe₃), C₍₁₋₃₎alkyl, C₍₁₋₃₎hydroxyalkyl,C₍₁₋₃₎thioalkyl, C₍₁₋₃₎alkylamino, benzyldihydrocinnamoyl group,benzoyldihydrocinnamido group, heterocyclic group and carbocyclic group.

The heterocyclic group or carbocyclic group is optionally substitutedwith one or more members of the group consisting of halo, hydroxyl,nitro (e.g., —NO₂), SO₂NH₂, C₍₁₋₆₎alkyl, C₍₁₋₆₎haloalkyl, C₍₁₋₈₎alkoxyl,C₍₁₋₁₁₎alkoxyalkyl, C₍₁₋₆₎alkylamino, and C₍₁₋₆₎aminoalkyl.

Preferably, both X and Y are not N(R₃) when Z is C(R₃) and R₃ is H orC₍₁₋₃₎alkyl.

More preferably, R₁ is not an ω-1 secondary alcohol substitutedC₍₅₋₈₎alkyl when both X and Y are N(R₃), Z is C(R₃) and R₃ is H orC₍₁₋₃₎alkyl.

In a another preferred embodiment, the present invention is directed toa therapeutic compound, pharmaceutically acceptable derivatives (e.g.,racemic mixtures, resolved enantiomers, diastereomers, tautomers, saltsand solvates thereof) or prodrugs thereof, having the following FormulaII:

wherein R₄, R₅ and R₆ are independently selected from a member of thegroup consisting of hydrogen, halo, oxo, C₍₁₋₂₀₎alkyl,C₍₁₋₂₀₎hydroxyalkyl, C₍₁₋₂₀₎thioalkyl, C₍₁₋₂₀₎alkylamino,C₍₁₋₂₀₎alkylaminoalkyl, C₍₁₋₂₀₎aminoalkyl, C₍₁₋₂₀₎aminoalkoxyalkenyl,C₍₁₋₂₀₎aminoalkoxyalkynyl, C₍₁₋₂₀₎diaminoalkyl, C₍₁₋₂₀₎triaminoalkyl,C₍₁₋₂₀₎tetraaminoalkyl, C₍₃₋₁₅₎aminodialkoxyamino,C₍₅₋₁₅₎aminotrialkoxyamino, C₍₁₋₂₀₎alkylamido, C₍₁₋₂₀₎alkylamidoalkyl,C₍₁₋₂₀₎amidoalkyl, C₍₁₋₂₀₎acetamidoalkyl, C₍₁₋₂₀₎alkenyl,C₍₁₋₂₀₎alkynyl, C₍₃₋₈₎alkoxyl, C₍₁₋₁₁₎alkoxyalkyl, andC₍₁₋₂₀₎dialkoxyalkyl.

Each R₄, R₅ and R₆ is optionally substituted with one or more members ofthe group consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl,biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group,cyano (e.g., NC—), cyanamido (e.g., NCNH—), cyanato (e.g., NCO—), sulfo,sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl,sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono, N—OH,—Si(CH₃)₃, C₍₁₋₃₎alkyl, C₍₁₋₃₎hydroxyalkyl, C₍₁₋₃₎thioalkyl,C₍₁₋₃₎alkylamino, benzyldihydrocinnamoyl group, benzoyldihydrocinnamidogroup, heterocyclic group and carbocyclic group.

The heterocyclic group or carbocyclic group is optionally substitutedwith one or more members of the group consisting of halo, hydroxyl,nitro (e.g., —NO₂), SO₂NH₂, C₍₁₋₆₎alkyl, C₍₁₋₆₎haloalkyl, C₍₁₋₈₎alkoxyl,C₍₁₋₁₁₎alkoxyalkyl, C₍₁₋₆₎alkylamino, and C₍₁₋₆₎aminoalkyl. In apreferred embodiment, each R₄, R₅ and R₆ are not simultaneously methyl.

In a preferred embodiment, both R₄ and R₅ are not methyl when R₆ is H.

In another preferred embodiment, R₆ is not methyl when R₄ is methylfuryland R₅ is H.

In a further preferred embodiment, R₆ is not propyl or isopropyl when R₄is methyl and R₅ is H.

In a still further preferred embodiment, R₄ is not acetamidohexyl whenR₅ is methyl and R₆ is H.

Suitable examples of R₂, and R₃ groups of Formula I and R₄, R₅ and R₆groups of Formula II include, without limitation, members selected fromthe group consisting of 1-adamantanemethyl, 1-phenylcyclopropyl,1-phenylproply, 1-propenyl, 2-bromopropyl, 2-buten-2-yl, 2-butyl,2-cyclohexylethyl, 2-cyclopentylethyl, 2-furyl, 2-hydroxyethyl,2-hydroxystyryl, 2-methoxyethyl, 2-methoxystyryl, 2-methylbutyl,2-methylcyclopropyl, 2-norboranemethyl, 2-phenylpropyl, 2-propenyl,2-propyl, 2-thienyl, 2-trifluoromethylstyryl, 3,4,5-triethoxyphenyl,3,4,5-trimethoxyphenyl, 3,4-dichlorobenzyl, 3,4-dichlorophenyl,3,4-difluorophenyl, 3,4-difluorobenzyl, 3,4-dihydroxybenzyl,3,4-dihydroxystyryl, 3,4-dimethoxybenzyl, 3,4-dimethoxyphenethyl,3,4-dimethoxyphenyl, 3,4-dimethoxystyryl, 3,4-dimethylphenyl,3,5-bis(trifluoromethyl)-benzyl, 3,5-dimethylphenyl,3-bromo-4-methylphenyl, 3-bromobenzyl, 3-cyclohexylpropyl,3-dimethylaminobutyl, 3-fluoro-4-methylphenyl, 3-fluorobenzyl,3-hepten-3-yl, 3-hydroxy-n-butyl, 3-hydroxypropyl,3-iodo-4-methylphenyl, 3-methoxy-4-methylphenyl, 3-methoxybenzyl,3-methylbenzyl, 3-phenylpropyl, 3-trifluoromethylbenzyl,4′-ethyl-4-biphenyl, 4-biphenyl, 4-bromobenzyl, 4-bromophenyl,4-butylphenyl, 4-chloropentyl, 4-chlorostyryl, 4-ethoxybenzyl,4-fluorobenzyl, 4-fluorophenyl, 4-hydroxyphenyl, 4-isobutylphenethyl,4-isopropylphenyl, 4-methoxybenzyl, 4-methoxy-n-butyl, 4-methylbenzyl,4-methylcyclohexanemethyl, 4-methylcyclohexyl, 4-phenylbenzyl,4-t-butylcyclohexyl, 4-vinylphenyl, 5-hydroxyhexyl, alpha-methylstyryl,benzyl, cyclobutyl, cycloheptyl, cyclohexyl, cyclohexylmethyl,cyclopentyl, ethyl, hexyl, isobutyl, isopropyl, isovaleryl, m-anisyl,methyl, m-tolyl, n-butyl, n-propyl, p-anisyl, phenethyl, phenyl, propyl,p-tolyl, styryl, t-butyl, and the like.

Preferred R₂, R₃, R₄, R₅ and R₆ groups include, without limitation,members selected from the group consisting of methyl, ethyl, oxo,isopropyl, n-propyl, isobutyl, n-butyl, t-butyl, 2-hydroxyethyl,3-hydroxypropyl, 3-hydroxy-n-butyl, 2methoxyethyl, 4-methoxy-n-butyl,5-hydroxyhexyl, 2-bromopropyl, 3-dimethylaminobutyl, 4-chloropentyl,methylamino, aminomethyl, methylphenyl, and the like.

In accordance with the principles of the present invention, the noveltherapeutic compounds disclosed herein may contain one or moreasymmetrically substituted carbon atoms and, thus, may occur asracemates and racemic mixtures, single enantiomers, diastereomericmixtures and individual diastereomers. Each stereogenic carbon may be ofthe R or S configuration. Many geometric isomers of olefins, C—N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. It is well known in the art how to prepare optically activeforms, such as by resolution of racemic forms or by synthesis fromoptically active starting materials. All chiral, diastereomeric, racemicforms and all geometric forms of a structure are intended to beencompassed within the present invention unless a specificstereochemistry or isomer form is specifically indicated.

The compounds of the present invention may be modified by appendingappropriate functionalites to enhance selective biological properties.Such modifications are known in the art and include, without limitation,those which increase penetration into a given biological compartment(e.g., blood, lymphatic system, central nervous system), increase oralor intravenous bioavailability, increase solubility to allowadministration by injection, alter metabolism, alter rate of excretion,etc.

Definitions

“Stable compound”, as used herein, is a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into an efficacious therapeutic agent, i.e.,possesses stability that is sufficient to allow manufacture and thatmaintains the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a mammal or for use in affinitychromatography applications). Typically, such compounds are stable at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week. “Metabolicallystable compound” denotes a compound that remains bioavailable whenorally ingested by a mammal.

“Substituted”, as used herein, whether express or implied and whetherpreceded by “optionally” or not, means that any one or more hydrogen onthe designated atom (C, N, etc.) is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.For instance, when a CH₂ is substituted by a keto substituent (═O), then2 hydrogens on the atom are replaced. It should be noted that when asubstituent is listed without indicating the atom via which suchsubstituent is bonded, then such substituent may be bonded via any atomin such substituent. For example, when the substituent is piperazinyl,piperidinyl, or tetrazolyl, unless specified otherwise, saidpiperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest ofthe compound of Formula I or II, as well as the R₂, R₃, R₄, R₅ and R₆groups substituted thereon, via any atom in such piperazinyl,piperidinyl, tetrazolyl group. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds. Further, when more than one position in a given structure maybe substituted with a substituent selected from a specified group, thesubstituents may be either the same or different at every position.Typically, when a structure may be optionally substituted, 0-15substitutions are preferred, 0-5 substitutions are more preferred, and0-1 substitution is most preferred.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includes,without limitation, instances where said event or circumstance occursand instances in which it does not. For example, optionally substitutedalkyl means that alkyl may or may not be substituted by those groupsenumerated in the definition of substituted alkyl.

“Acyl” denotes a radical provided by the residue after removal ofhydroxyl from an organic acid. Examples of such acyl radicals include,without limitation, alkanoyl and aroyl radicals. Examples of such loweralkanoyl radicals include, without limitation, formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,trifluoroacetyl.

“Acylamino” denotes an N-substituted amide, i.e., RC(O)—NH andRC(O)—NR′—. A non-limiting example is acetamido.

“Acyloxy” means 1 to about 4 carbon atoms. Suitable examples include,without limitation, alkanoyloxy, benzoyloxy and the like.

“Alkyl” or “lower alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon radicals/groups havingthe specified number of carbon atoms. In particular, “alkyl” refers to amonoradical branched or unbranched saturated hydrocarbon chain,preferably having from 1 to 40 carbon atoms, more preferably 1 to 10carbon atoms, even more preferably 1 to 6 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tert-butyl,n-hexyl, n-octyl, n-decyl, n-dodecyl, 2-ethyldodecyl, tetradecyl, andthe like, unless otherwise indicated.

“Substituted alkyl” refers to an alkyl group as defined above havingfrom 1 to 5 substituents selected, without limitation, from the groupconsisting of alkoxyl, substituted alkoxyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxyl, aminoacyl, aminoacyloxyl, oxyaminoacyl, azido, cyano, halogen,hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxyl,thioheteroaryloxyl, thioheterocyclooxyl, thiol, thioalkoxyl, substitutedthioalkoxyl, aryl, aryloxyl, heteroaryl, heteroaryloxyl, heterocyclic,heterocyclooxyl, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-aryl, —SO₂-heteroaryl, and—NR^(a)R^(b), wherein R^(a) and R^(b) may be the same or different andare chosen from hydrogen, optionally substituted alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic group.

“Alkylamino” denotes amino groups which have been substituted with oneor two alkyl radicals. Preferred are “lower N-alkylamino” radicalshaving alkyl portions having 1 to 6 carbon atoms. Suitable loweralkylamino may be mono or dialkylamino such as N-methylamino,N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.

“Alkylaminoalkyl” embraces radicals having one or more alkyl radicalsattached to an aminoalkyl radical.

“Alkylaminocarbonyl” denotes an aminocarbonyl group which has beensubstituted with one or two alkyl radicals on the amino nitrogen atom.Preferred are “N-alkylaminocarbonyl” “N,N-dialkylaminocarbonyl”radicals. More preferred are “lower N-alkylaminocarbonyl” “lowerN,N-dialkylaminocarbonyl” radicals with lower alkyl portions as definedabove.

“Alkylcarbonyl”, “arylcarbonyl” and “aralkylcarbonyl” include radicalshaving alkyl, aryl and aralkyl radicals, as defined above, attached viaan oxygen atom to a carbonyl radical. Examples of such radicals include,without limitation, substituted or unsubstituted methylcarbonyl,ethylcarbonyl, phenylcarbonyl and benzylcarbonyl.

“Alkylsulfinyl” embraces radicals containing a linear or branched alkylradical, of one to ten carbon atoms, attached to a divalent —S(═O)—radical. More preferred alkylsulfinyl radicals are “lower alkylsulfinyl”radicals having alkyl radicals of one to six carbon atoms. Examples ofsuch lower alkylsulfinyl radicals include, without limitation,methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.

“Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. More preferred alkylsulfonyl radicalsare “lower alkylsulfonyl” radicals having one to six carbon atoms.Examples of such lower alkylsulfonyl radicals include, withoutlimitation, methylsulfonyl, ethylsulonyl and propylsulfonyl. The“alkylsulfonyl” radicals may be further substituted with one or morehalo atoms, such as fluoro, chloro or bromo, to providehaloalkylsulfonyl radicals.

“Alkylthio” embraces radicals containing a linear or branched alkylradical, of one to about ten carbon atoms attached to a divalent sulfuratom. More preferred alkylthio radicals are “lower alkylthio” radicalshaving alkyl radicals of one to six carbon atoms. Examples of such loweralkylthio radicals are methylthio, ethylthio, propylthio, butylthio andhexylthio.

“Alkylthioalkyl” embraces radicals containing an alkylthio radicalattached through the divalent sulfur atom to an alkyl radical of one toabout ten carbon atoms. More preferred alkylthioalkyl radicals are“lower alkylthioalkyl” radicals having alkyl radicals of one to sixcarbon atoms. Examples of such lower alkylthioalkyl radicals include,without limitation, methylthiomethyl.

“Alkylene” refers to a diradical of a branched or unbranched saturatedhydrocarbon chain, preferably having from 1 to 40 carbon atoms, morepreferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbonatoms. This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g. —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

“Substituted alkylene“refers to: (1) an alkylene group as defined abovehaving from 1 to 5 substituents selected from a member of the groupconsisting of alkoxyl, substituted alkoxyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxyl, aminoacyl, aminoacyloxyl, oxyacylamino, azido, cyano, halogen,hydroxyl, keto, thioketo, carboxyl, carboxylalkyl,thiol, thioalkoxyl,substituted thioalkoxyl, aryl, aryloxyl, thioaryloxyl, heteroaryl,heteroaryloxyl, thioheteroaryloxyl, heterocyclic, heterocyclooxyl,thioheterocyclooxyl, nitro, and —NR^(a)R^(b), wherein R^(a) and R^(b)may be the same or different and are chosen from hydrogen, optionallysubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,heteroaryl and heterocyclic. Additionally, such substituted alkylenegroups include, without limitation, those where 2 substituents on thealkylene group are fused to form one or more cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclicor heteroaryl groups fused to the alkylene group; (2) an alkylene groupas defined above that is interrupted by 1-20 atoms independently chosenfrom oxygen, sulfur and NR^(a), where R^(a) is chosen from hydrogen,optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic, orgroups selected from carbonyl, carboxyester, carboxyamide and sulfonyl;or (3) an alkylene group as defined above that has both from 1 to 5substituents as defined above and is also interrupted by 1 to 20 atomsas defined above. Examples of substituted alkylenes are chloromethylene(—CH(C1)—), aminoethylene (—CH(NH₂)CH₂—), 2-carboxypropylene isomers(—CH₂CH(CO₂H)CH₂—), ethoxyethyl (—CH₂CH₂O—CH₂CH₂—),ethylmethylaminoethyl (—CH₂CH₂N(CH₃)CH₂CH₂—),1-ethoxy-2-(2-ethoxy-ethoxy)ethane (—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—OCH₂CH₂—),and the like.

“Alkynyl” is intended to include hydrocarbon chains of either a straightor branched configuration and one or more triple carbon-carbon bondswhich may occur in any stable point along the chain, such as ethynyl,propynyl and the like. For example, alkynyl refers to an unsaturatedacyclic hydrocarbon radical in so much as it contains one or more triplebonds, such radicals containing about 2 to about 40 carbon atoms,preferably having from about 2 to about 10 carbon atoms and morepreferably having 2 to about 6 carbon atoms. Non-limiting examples ofsuitable alkynyl radicals include, ethynyl, propynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl,hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.

“Alicyclic hydrocarbon” means a aliphatic radical in a ring with 3 toabout 10 carbon atoms, and preferably from 3 to about 6 carbon atoms.Examples of suitable alicyclic radicals include, without limitation,cyclopropyl, cyclopropylenyl, cyclobutyl, cyclopentyl, cyclohexyl,2-cyclohexen-1-ylenyl, cyclohexenyl and the like. “Alkoxyalkyl” embracesalkyl radicals having one or more alkoxy radicals attached to the alkylradical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.The “alkoxy” radicals may be further substituted with one or more haloatoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals.More preferred haloalkoxy radicals are “lower haloalkoxy” radicalshaving one to six carbon atoms and one or more halo radicals. Examplesof such radicals include, without limitation, fluoromethoxy,chloromethoxy, trifluoromethoxy, trifluoromethoxy, fluoroethoxy andfluoropropoxy. Further, “alkoxycarbonyl” means a radical containing analkoxy radical, as defined above, attached via an oxygen atom to acarbonyl radical. More preferred are “lower alkoxycarbonyl” radicalswith alkyl portions having 1 to 6 carbons. Examples of such loweralkoxycarbonyl (ester) radicals include, without limitation, substitutedor unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl and hexyloxycarbonyl.

“Aminoalkyl” embraces alkyl radicals substituted with amino radicals.More preferred are “lower aminoalkyl” radicals. Examples of suchradicals include, without limitation, aminomethyl, aminoethyl, and thelike.

“Aminocarbonyl” denotes an amide group of the formula —C(═O)NH₂.

“Aralkoxy” embraces aralkyl radicals attached through an oxygen atom toother radicals.

“Aralkoxyalkyl” embraces aralkoxy radicals attached through an oxygenatom to an alkyl radical.

“Aralkyl” embraces aryl-substituted alkyl radicals such as benzyl,diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. Thearyl in said aralkyl may be additionally substituted with halo, alkyl,alkoxy, halkoalkyl and haloalkoxy.

“Aralkylamino” embraces aralkyl radicals attached through an nitrogenatom to other radicals.

“Aralkylthio” embraces aralkyl radicals attached to a sulfur atom.

“Aralkylthioalkyl” embraces aralkylthio radicals attached through asulfur atom to an alkyl radical.

“Aromatic hydrocarbon radical” means 4 to about 16 carbon atoms,preferably 6 to about 12 carbon atoms, more preferably 6 to about 10carbon atoms. Examples of suitable aromatic hydrocarbon radicalsinclude, without limitation, phenyl, naphthyl, and the like.

“Aroyl” embraces aryl radicals with a carbonyl radical as defined above.Examples of aroyl include, without limitation, benzoyl, naphthoyl, andthe like and the aryl in said aroyl may be additionally substituted.

“Arylamino” denotes amino groups which have been substituted with one ortwo aryl radicals, such as N-phenylamino. Arylamino radicals may befurther substituted on the aryl ring portion of the radical.

“Aryloxyalkyl” embraces radicals having an aryl radical attached to analkyl radical through a divalent oxygen atom.

“Arylthioalkyl” embraces radicals having an aryl radical attached to analkyl radical through a divalent sulfur atom.

“Carbonyl”, whether used alone or with other terms, such as“alkoxycarbonyl”, denotes —(C═O)—.

“Carboxy” or “carboxyl”, whether used alone or with other terms, such as“carboxyalkyl”, denotes —CO₂H.

“Carboxyalkyl” embraces alkyl radicals substituted with a carboxyradical. More preferred are “lower carboxyalkyl” which embrace loweralkyl radicals as defined above, and may be additionally substituted onthe alkyl radical with halo. Examples of such lower carboxyalkylradicals include, without limitation, carboxymethyl, carboxyethyl andcarboxypropyl.

“Cycloalkenyl” embraces partially unsaturated carbocyclic radicalshaving three to twelve carbon atoms. More preferred cycloalkenylradicals are “lower cycloalkenyl” radicals having four to about eightcarbon atoms. Examples of such radicals include, without limitation,cyclobutenyl, cyclopentenyl and cyclohexenyl.

“Cycloalkyl” embraces saturated carbocyclic radicals having three totwelve carbon atoms. More preferred cycloalkyl radicals are “lowercycloalkyl” radicals having three to about eight carbon atoms. Examplesof such radicals include, without limitation, cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

“Hydroxyalkyl” embraces linear or branched alkyl radicals having one toabout twenty carbon atoms any one of which may be substituted with oneor more hydroxyl radicals. Preferred hydroxyalkyl radicals are “lowerhydroxyalkyl” radicals having one to six carbon atoms and one or morehydroxyl radicals. Non-limiting examples of such radicals includehydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl andhydroxyhexyl.

“Sulfamyl”, “aminosulfonyl” and “sulfonamidyl” denote NH₂O₂S—.

“Sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

“Alkenyl” is intended to include hydrocarbon chains of either a straightor branched configuration and one or more unsaturated carbon-carbonbonds which may occur in any stable point along the chain. For example,alkenyl refers to an unsaturated acyclic hydrocarbon radical in so muchas it contains at least one double bond. Such radicals containing fromabout 2 to about 40 carbon atoms, preferably from about 2 to about 10carbon atoms and more preferably about 2 to about 6 carbon atoms.Non-limiting examples of suitable alkenyl radicals include propylenyl,buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yl,3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl, and thelike

“Alkoxyl” represents an alkyl group of indicated number of carbon atomsattached through an oxygen bridge. “Alkoxy” and “alkyloxy” embracelinear or branched oxy-containing radicals each having alkyl portions ofone to about ten carbon atoms. More preferred alkoxy radicals are “loweralkoxy” radicals having one to six carbon atoms. Examples of suchradicals include, Without limitation, methoxy, ethoxy, propoxy, butoxyand tert-butoxy.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to20 carbon atoms having a single ring (e.g.,.phenyl) or multiplecondensed (fused) rings (e.g., naphthyl or anthryl). “aryl” embracesaromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indaneand biphenyl. Unless otherwise constrained by the definition for thearyl substituent, such aryl groups can optionally be substituted withfrom 1 to 5 substituents selected from a member of the group consistingof acyloxyl, hydroxyl, thiol, acyl, alkyl, alkoxyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxyl,substituted alkenyl, substituted alkynyl, substituted cycloalkyl,substituted cycloalkenyl, aminoacyl, acylamino, alkaryl, aryl, aryloxyl,azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,heteroaryloxyl, heterocyclic, heterocyclooxyl, aminoacyloxyl,oxyacylamino, thioalkoxyl, substituted thioalkoxyl, thioaryloxyl,thioheteroaryloxyl, —SO-alkyl, —SO-substituted alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl,—SO₂-heteroaryl, trihalomethyl, NR^(a)R^(b), wherein R^(a) and R^(b) maybe the same or different and are chosen from hydrogen, optionallysubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,heteroaryl and heterocyclic. Preferred aryl substituents include,without limitation, without limitation, alkyl, alkoxyl, halo, cyano,nitro, trihalomethyl, and thioalkoxy (i.e., —S-alkyl).

“N-arylaminoalkyl” and “N-aryl-N-alkyl-aminoalkyl” denote amino groupswhich have been substituted with one aryl radical or one aryl and onealkyl radical, respectively, and having the amino group attached to analkyl radical. Examples of such radicals include, without limitation,N-phenylaminomethyl and N-phenyl-N-methylaminomethyl.

“Carbocycle” or carbocyclic group” is intended to mean any stable 3 to 7membered monocyclic or bicyclic or 7 to 14 membered bicyclic ortricyclic or an up to 26 membered polycyclic carbon ring, any of whichmay be saturated, partially unsaturated, or aromatic.

“substituted carbocycle” or “substituted carbocyclic group” refers tocarbocyclic groups having from 1 to 5 substituents selected from amember of the group consisting of alkoxyl, substituted alkoxyl,cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxyl, amino, aminoacyl, aminoacyloxyl, oxyaminoacyl, azido, cyano,halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl,thioaryloxyl, thioheteroaryloxyl, thioheterocyclooxyl, thiol,thioalkoxyl, substituted thioalkoxyl, aryl, aryloxyl, heteroaryl,heteroaryloxyl, heterocyclic, heterocyclooxyl, hydroxyamino,alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl,—SO₂-heteroaryl, and NR^(a)N^(b), wherein R^(a) and R^(b) may be thesame or different and are chosen from hydrogen, optionally substitutedalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl andheterocyclic. Preferred examples of carbocyclic groups include, withoutlimitation, members selected from the group consisting of adamantyl,anthracenyl, benzamidyl, benzyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.1]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.0]heptanyl,bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl, biphenyl, biscyclooctyl,cyclobutanyl (cyclobutyl), cyclobutenyl, cycloheptanyl (cycloheptyl),cycloheptenyl, cyclohexanedionyl, cyclohexenyl, cyclohexyl,cyclooctanyl, cyclopentadienyl, cyclopentanedionyl, cyclopentenyl,cyclopentyl, cyclopropyl, decalinyl, 1,2-diphenylethanyl, indanyl,1-indanonyl, indenyl, naphthyl, napthlalenyl, phenyl, resorcinolyl,stilbenyl, tetrahydronaphthyl (tetralin), tetralinyl, tetralonyl,tricyclododecanyl, and the like.

“Cycloalkyl” is intended to include saturated ring groups, includingmono-, bi- or poly-cyclic ring systems, such as, without limitation,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and adamantyl. “Bicycloalkyl” is intended to includesaturated bicyclic ring groups such as, without limitation,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, and so forth.

“Halo” or halogen” as used herein refers to fluoro, chloro, bromo andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate and thelike.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Haloalkyl embracesradicals wherein any one or more of the alkyl carbon atoms issubstituted with halo as defined above. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have either an iodo, bromo, chloro orfluoro atom within the radical. Dihalo and polyhaloalkyl radicals mayhave two or more of the same halo atoms or a combination of differenthalo radicals. “Lower haloalkyl” embraces radicals having 1-6 carbonatoms. Non-limiting examples of haloalkyl radicals include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl.

“Heterocycle” or “heterocyclic group” refers to a saturated orunsaturated group having a single ring, multiple condensed rings ormultiple covalently joined rings, from 1 to 40 carbon atoms and from 1to 10 hetero ring atoms, preferably 1 to 4 hetero ring atoms, selectedfrom nitrogen, sulfur, phosphorus, and/or oxygen. Preferably,“heterocycle” or “heterocyclic group” means a stable 5 to 7 memberedmonocyclic or bicyclic or 7 to 10 membered bicyclic heterocyclic ringthat may be saturated, partially unsaturated, or aromatic, and thatcomprises carbon atoms and from 1 to 4 heteroatoms independentlyselected from a member of the group consisting of nitrogen, oxygen andsulfur and wherein the nitrogen and sulfur heteroatoms are optionally beoxidized and the nitrogen heteroatom may optionally be quaternized, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic groupsmay be substituted on carbon or on a nitrogen, sulfur, phosphorus,and/or oxygen heteroatom so long as the resulting compound is stable.Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, and preferably 1 to 3 substituents. Suitable, but non-limiting,examples of such substituents include members selected from the groupconsisting of alkoxyl, substituted alkoxyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxyl, aminoacyl, aminoacyloxyl, oxyaminoacyl, cyano, halogen,hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxyl,thioheteroaryloxyl, thioheterocyclooxyl, thiol, thioalkoxyl, substitutedthioalkoxyl, aryl, aryloxyl, heteroaryl, heteroaryloxyl, heterocyclic,heterocyclooxyl, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO,-heteroaryl, and NR^(a)N^(b),wherein R^(a) and R^(b) may be the same or different and are chosen fromhydrogen, optionally substituted alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

Suitable examples of such heterocyclic groups include, withoutlimitation, acridinyl, acridonyl, adeninyl, alkylpyridinyl, alloxanyl,alloxazinyl, anthracenyl, anthranilyl, anthraquinonyl, anthrenyl,ascorbyl, azaazulenyl, azabenzanthracenyl, azabenzanthrenyl,azabenzonaphthenyl, azabenzophenanthrenyl, azachrysenyl, azacyclazinyl,azaindolyl, azanaphthacenyl, azanaphthalenyl, azaphenoxazinyl, azapinyl,azapurinyl, azapyrenyl, azatriphenylenyl, azepinyl, azetidinedionyl,azetidinonyl, azetidinyl, azinoindolyl, azinopyrrolyl, azinyl,aziridinonyl, aziridinyl, azirinyl, azocinyl, azoloazinyl, azolyl,barbituric acid, benzacridinyl, benzazapinyl, benzazinyl,benzimidazolethionyl, benzimidazolonyl, benzimidazolyl,benzisothiazolyl, benzisoxazolyl, benzocinnolinyl, benzodiazocinyl,benzodioxanyl, benzodioxolanyl, benzodioxolyl, benzofuranyl(benzofuryl), benzofuroxanyl, benzonaphthyridinyl, benzopyranonyl(benzopyranyl), benzopyridazinyl, benzopyronyl, benzoquinolinyl,benzoquinolizinyl, benzothiadiazinyl, benzothiazepinyl, benzothiazinyl,benzothiazolyl, benzothiepinyl, benzothiophenyl, benzotriazepinonyl,benzotriazolyl, benzoxadizinyl, benzoxazinyl, benzoxazolinonyl,benzoxazolyl, benzylisoquinolinyl, beta-carbolinyl, biotinyl,bipyridinyl, butenolidyl, butyrolactonyl, caprolactamyl, carbazolyl, 4aH-carbazolyl, carbolinyl, catechinyl, chromanyl, chromenopyronyl,chromonopyranyl, chromylenyl, cinnolinyl, coumarinyl, coumaronyl,decahydroquinolinyl, decahydroquinolonyl, depsidinyl, diazaanthracenyl,diazaphenanthrenyl, diazepinyl, diazinyl, diaziridinonyl, diaziridinyl,diazirinyl, diazocinyl, dibenzazepinyl, dibenzofuranyl,dibenzothiophenyl, dibenzoxazepinyl, dichromylenyl,dihydrobenzimidazolyl, dihydrobenzothiazinyl, dihydrofuranyl,dihydroisocoumarinyl, dihydroisoquinolinyl, dihydrooxazolyl,dihydropyranyl, dihydropyridazinyl, dihydropyridinyl, dihydropyridonyl,dihydropyrimidinyl, dihydropyronyl, dihydrothiazinyl,dihydrothiopyranyl, dihydroxybenzenyl, dimethoxybenzenyl,dimethylxanthinyl, dioxadiazinyl, dioxanthylenyl, dioxanyl, dioxenyl,dioxepinyl, dioxetanyl, dioxinonyl, dioxinonyl, dioxiranyl, dioxolanyl,dioxolonyl, dioxolyl, dioxopiperazinyl, diprylenyl, dipyrimidopyrazinyl,dithiadazolyl, dithiazolyl, 2H,6H-1,5,2-dithiazinyl, dithietanyl,dithiolanyl, dithiolenyl, dithiolyl, enantholactamyl, episulfonyl,flavanyl, flavanyl, flavinyl, flavonyl, fluoranyl, fluorescienyl,furandionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl(furyl), furazanyl, furfuryl, furopyranyl, furopyrimidinyl, furopyronyl,furoxanyl, glutarimidyl, glycocyamidinyl, guaninyl, heteroazulenyl,hexahydropyrazinoisoquinolinyl, hexahydropyridazinyl, homophthalimidyl,hydantoinyl, hydrofuranyl, hydrofurnanonyl, hydroimidazolyl,hydroindolyl, hydropyranyl, hydropyrazinyl, hydropyrazolyl,hydropyridazinyl, hydropyridinyl, hydropyrimidinyl, hydropyrrolyl,hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, hydrotriazolyl,hydroxytrizinyl, imidazolethionyl, imidazolidinyl, imidazolinyl,imidazolonyl, imidazolyl, imidazoquinazolinyl, irnidazothiazolyl,indazolebenzopyrazolyl, indazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizidinyl, indolizinyl, indolonyl, indolyl, 3H-indolyl, indoxazenyl,inosinyl, isatinyl, isatogenyl, isoalloxazinyl, isobenzofurandionyl,isobenzofuranyl, isochromanyl, isoflavonyl, isoindolinyl (isoindolyl),isoindolobenzazepinyl, isoquinolinyl, isoquinuclidinyl, isothiazolyl,isoxazolidinyl, isoxazolinonyl, isoxazolinyl, isoxazolonyl, isoxazolyl,lactamyl, lactonyl, lumazinyl, maleimidyl, methylbenzamidyl,methylbenzoyleneureayl, methyldihydrouracilyl,methyldioxotetrahydropteridinyl, methylpurinyl, methylthyminyl,methylthyminyl, methyluracilyl, methylxanthinyl, monoazabenzonaphthenyl,morpholinyl (morpholino), naphthacenyl, naphthalenyl, naphthimidazolyl,naphthimidazopyridinedionyl, naphthindolizinedionyl,naphthodihydropyranyl, naphthofuranyl, naphthothiophenyl,naphthylpyridinyl, naphthyridinyl, octahydroisoquinolinyl,octylcarboxamidobenzenyl, oroticyl, oxadiazinyl, oxadiazolyl,oxathianyl, oxathiazinonyl, oxathietanyl, oxathiiranyl, oxathiolanyl,oxatriazolyl, oxazinonyl, oxaziranyl, oxaziridinyl, oxazolidinonyl,oxazolidinyl, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazolonyl,oxazolopyrimidinyl, oxazolyl, oxepinyl, oxetananonyl, oxetanonyl,oxetanyl, oxindolyl, oxiranyl, oxolenyl, pentazinyl, pentazolyl,perhydroazolopyridinyl, perhydrocinnolinyl, perhydroindolyl,perhydropyrroloazinyl, perhydropyrrolooxazinyl,perhydropyrrolothiazinyl, perhydrothiazinonyl, perimidinyl, petrazinyl,phenanthraquinonyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl,phenazinyl, phenothiazinyl, phenoxanthinyl, phenoxazinyl, phenoxazonyl,phthalazinyl, phthalideisoquinolinyl, phthalimidyl, phthalonyl,piperazindionyl, piperazinodionyl, piperazinyl, piperidinyl,piperidonyl, 4-piperidonyl, polyoxadiazolyl, polyquinoxalinyl, prolinyl,prylenyl, pteridinyl, pterinyl, purinyl, pyradinyl, pyranoazinyl,pyranoazolyl, pyranonyl, pyranopyradinyl, pyranopyrandionyl,pyranopyridinyl, pyranoquinolinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolidonyl, pyrazolinonyl, pyrazolinyl, pyrazolobenzodiazepinyl,pyrazolonyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl,pyrazolyl, pyrenyl, pyridazinyl, pyridazonyl, pyridinethionyl,pyridinonaphthalenyl, pyridinopyridinyl, pyridocolinyl, pyridoindolyl,pyridopyrazinyl, pyridopyridinyl, pyridopyrimidinyl, pyridopyrrolyl,pyridoquinolinyl, pyridyl (pyridinyl), pyrimidinethionyl, pyrimidinyl,pyrimidionyl, pyrimidoazepinyl, pyrimidopteridinyl, pyronyl,pyrrocolinyl, pyrrolidinyl, 2-pyrrolidinyl, pyrrolinyl, pyrrolizidinyl,pyrrolizinyl, pyrrolobenzodiazepinyl, pyrrolodiazinyl, pyrrolonyl,pyrrolopyrimidinyl, pyrroloquinolonyl, pyrrolyl, 2H-pyrrolyl,quinacridonyl, quinazolidinyl, quinazolinonyl, quinazolinyl, quinolinyl,quinolizidinyl, quinolizinyl, 4H-quinolizinyl, quinolonyl, quinonyl,quinoxalinyl, quinuclidinyl, quinuclidinyl, rhodaminyl, spirocoumaranyl,succinimidyl, sulfolanyl, sulfolenyl, sultamyl, sultinyl, sultonyl,sydononyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydrooxazolyl, tetrahydropyranyl, tetrahydropyrazinyl,tetrahydropyridazinyl, tetrahydropyridinyl, tetrahydroquinolinyl,tetrahydroquinoxalinyl, tetrahydrothiapyranyl, tetrahydrothiazolyl,tetrahydrothiophenyl, tetrahydrothiopyranonyl, tetrahydrothiopyranyl,tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl, tetronyl,thiabenzenyl, thiachromanyl, thiadecalinyl, thiadiazinyl,6H-1,2,5-thiadiazinyl, thiadiazolinyl, thiadiazolyl, thiadioxazinyl,thianaphthenyl, thianthrenyl, thiapyranyl, thiapyrohyl, thiatriazinyl,thiatriazolyl, thiazepinyl, thiazetidinyl, thiazinyl, thiaziridinyl,thiazolidinonyl, thiazolidinyl, thiazolinonyl, thiazolinyl,thiazolobenzimidazolyl, thiazolopyridinyl, thiazolyl, thienopryidinyl,thienopyrimidinyl, thienopyrrolyl, thienothiophenyl, thienyl, thiepinyl,thietanyl, thiiranyl, thiochromenyl, thiocoumarinyl, thiolanyl,thiolenyl, thiolyl, thiophenyl, thiopyranyl, thyminyl,triazaanthracenyl, triazepinonyl, triazepinyl, triazinoindolyl,triazinyl, triazolinedionyl, triazolinyl, triazolopyridinyl,triazolopyrimidinyl, triazolyl, trioxanyl, triphenodioxazinyl,triphenodithiazinyl, trithiadiazepinyl, trithianyl, trixolanyl,trizinyl, tropanyl, uracilyl, xanthenyl, xanthinyl, xanthonyl,xanthydrolyl, xylitolyl, and the like as well as N-alkoxy-nitrogencontaining heterocycles. Preferred heterocyclic groups include, withoutlimitation, members of the group consisting of acridinyl, aziridinyl,azocinyl, azepinyl, benzimidazolyl, benzodioxolanyl, benzofuranyl,benzothiophenyl, carbazole, 4a H-carbazole, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, dioxoindolyl, furazanyl, furyl,furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthalenyl, naphthyridinyl, norbomanyl,norpinanyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, oxiranyl,perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenyl,phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, piperidyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyrenyl, pyridazinyl, pyridinyl, pyridyl, pyridyl,pyrimidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolonyl, pyrrolyl,2H-pyrrolyl, quinazolinyl, 4H-quinolizinyl, quinolinyl, quinoxalinyl,quinuclidinyl, 1-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,2H-,6H-1,5,2-dithiazinyl, thianthrenyl, thiazolyl, thienyl, thiophenyl,triazinyl, xanthenyl, xanthinyl, and the like.

“Pharmaceutically acceptable derivative” or “prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester, or otherderivative of a compound of the present invention which, uponadministration to a recipient, is capable of providing (directly orindirectly) a compound of this invention. Particularly favoredderivatives and prodrugs are those that increase the bioavailability ofthe compounds of this invention when such compounds are administered toa mammal (e.g., by allowing an orally administered compound to be morereadily absorbed into the blood) or that enhance delivery of the parentcompound to a biological compartment (e.g., the brain or lymphaticsystem) relative to the parent species. Prodrugs are considered to beany covalently bonded carriers which release the active parent drugaccording to Formula I or II in vivo when such prodrug is administeredto a mammalian subject. Preferred prodrugs include, without limitation,derivatives where a group that enhances aqueous solubility or activetransport through the gut membrane is appended to the structure ofFormula I or II. Prodrugs of the compounds of Formula I or II areprepared by modifying functional groups present in the compounds in sucha way that the modifications are cleaved, either in routine manipulationor in vivo, to the parent compounds. Prodrugs include compounds ofFormula I or II wherein hydroxyl, amino, sulfhydryl, or carboxyl groupsare bonded to any group that, when administered to a mammalian subject,cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of Formula I or II, and the like.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound of Formula I or II ismodified by making acid or base salts of the compound of Formula I orII. Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thecompounds of Formula I or II include the conventional nontoxic salts orthe quaternary ammonium salts of the compounds of Formula I or IIformed, for example, from nontoxic inorganic or organic acids. Forexample, such conventional non-toxic salts include, without limitation,those derived from inorganic acids such as acetic, 2-acetoxybenzoic,adipic, alginic, ascorbic, aspartic, benzoic, benzenesulfonic, bisulfic,butyric, citric, camphoric, camphorsulfonic, cyclopentanepropionic,digluconic, dodecylsulfanilic, ethane disulfonic, ethanesulfonilic,fumaric, glucoheptanoic, glutamic, glycerophosphic, glycolic,hemisulfanoic, heptanoic, hexanoic, hydrochloric, hydrobromic,hydroiodic, 2-hydroxyethanesulfonoic, hydroxymaleic, isethionic, lactic,malic, maleic, methanesulfonic, 2-naphthalenesulfonilic, nicotinic,nitric, oxalic, palmic, pamoic, pectinic, persulfanilic, phenylacetic,phosphoric, propionic, pivalic, propionate, salicylic, succinic,stearic, sulfuric, sulfamic, sulfanilic, tartaric, thiocyanic,toluenesulfonic, tosylic, undecanoatehydrochloric, and the like. Thepharmaceutically acceptable salts of the present invention can besynthesized from the compounds of Formula I or II which contain a basicor acidic moiety by conventional chemical methods, for example, byreacting the free base or acid with stoichiometric amounts of theappropriate base or acid, respectively, in water or in an organicsolvent, or in a mixture of the two (nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred) or byreacting the free base or acid with an excess of the desiredsalt-forming inorganic or organic acid or base in a suitable solvent orvarious combinations of solvents. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418, et al., the entire disclosure of which isincorporated herein by reference.

“Pharmaceutically effective” or “therapeutically effective” amount of acompound of the present invention is an amount that is sufficient toeffect treatment, as defined above, when administered to a mammal inneed of such treatment. The amount will vary depending upon the subjectand disease condition being treated, the weight and age of the subject,the severity of the disease condition, the manner of administration andthe like, which can be readily determined by one of skill in the art.

“Cellular process or activity mediated by IL-12” and “IL-12 mediatedprocesses and activities,” as used herein includes IL-12 initiatedcellular processes and activities, for example, the direct stimulationof IFN-γ production by resting T cells and NK cells. This term alsoincludes the IL-12 modulation of ongoing processes and activities, forexample, the enhancement of anti-CD3 induced IFN-γ secretion. Variousother IL-12-mediated processes and activities are intended to beencompassed by this term, for example, the differentiation of naive Tcells into Th1 cells; maintenance of the Th1 phenotype (e.g., high IFN-γproduction, low IL-4 production); proliferation of T cell blasts;enhancement of NK cell and CTL cytolytic activity, and the like. Foradditional examples, see Trinchieri, Annu. Rev. Immunol. 13: 251-76(1995).

“Treatment” refers to any treatment of an IL-12 mediated disease orcondition in a mammal, particularly a human, and includes, withoutlimitation: (i) preventing the disease or condition from occurring in asubject which may be predisposed to the condition but has not yet beendiagnosed with the condition and, accordingly, the treatment constitutesprophylactic treatment for the pathologic condition; (ii) inhibiting thedisease or condition, i.e., arresting its development; (iii) relievingthe disease or condition, i.e., causing regression of the disease orcondition; or (iv) relieving the symptoms resulting from the disease orcondition, e.g., relieving an inflammatory response without addressingthe underlining disease or condition.

The present invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. The basicnitrogen can be quatemized with any agents known to those of ordinaryskill in the art including, without limitation, lower alkyl halides,such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides;dialkyl sulfates including dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides; and aralkyl halides including benzyland phenethyl bromides. Water or oil-soluble or dispersible products maybe obtained by such quaternization.

In addition to their structural characteristics, the compounds of thepresent invention share an ability to inhibit IL-12 signaling. A skilledartisan or scientist using routine protocols or assays, such as theassays disclosed in the Examples below or in the literature, may readilyconfirm the utility of the compounds disclosed herein.

Without being bound by the above general structuraldescriptions/definitions, preferred compounds of the present inventionhaving utility for inhibiting IL-12 signaling according to the presentinvention, include, but are not limited to the following compounds. Itwill be appreciated, as noted above, that where an R or S enantiomer isexemplified for each particular compound, the corresponding S or Renantiomer, respectively, is also intended even though it may not bespecifically shown below.

More preferred compounds of the present invention having utility forinhibiting IL-12 signaling include without limitation, the following:

Further representative compounds of the present invention having utilityfor inhibiting IL-12 signaling in accordance with the present inventionare set forth below in Table I. The compounds in Table 1 have thefollowing general structure of Formula II:

It is noted that in Table 1, “Me” represents “—CH₃,” and “Et” represents“—CH₂CH₃.” In addition, although the below-exemplified moieties in Table1 are representative of R₄, R₅ and R₆ in Formula II, it will beunderstood that the exemplified moieties, without being limited by theabove description/definitions, are also representative of R₂ and R₃ inFormula I. TABLE 1 R₄ R₅ R₆ Me H

Me H

Me H

Me H

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Me H

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Me CH₂OEt

Me CH₂OEt

Me CH₂OEt

Me CH₂OEt

Me CH₂OEt

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Methods of Use

The present invention is also directed to a method for inhibiting IL-12signaling in a mammal having an inflammatory response (e.g., Th1cell-mediated). The methods of the present invention generally compriseadministering a pharmaceutically or therapeutically effective amount ofa compound as described herein to a patient in need of suchtreatmentwhereby IL-12 signaling is inhibited. The patient may be ahuman or non-human mammal. For example, a patient will need treatmentwhen exhibiting a deleterious inflammatory response in the course of adisease condition mediated by Th1 cells. Such need is determinable byskilled clinicians and investigators in the medical arts.

Preferred Th1 cell-mediated disease conditions that involve aninflammatory response may include, but are not limited to, the followingexemplary conditions: (1) inflammatory diseases or disorders, such as,for example, arthritis, asthma, chronic inflammatory diseases, chronicintestinal inflammation, psoriasis, septic shock, septicemia, and adultrespiratory distress syndrome; (2) autoimmune diseases or disorders,such as, for example, graft-versus-host disease (acute and/or chronic),autoimmune gastritis, autoimmune hemolytic anemia, autoimmuneneutropenia, chronic active hepatitis, chronic thyroiditis, inflammatorybowel disease (e.g., Crohn's Disease and ulcerative colitis), lupusdisorders (e.g., systemic lupus erythematosus), multiple sclerosis,myasthenia gravis, rheumatoid arthritis, scleroderma, thrombocytopenia,thyroid diseases (e.g., Graves' and Hashimoto's disease), type-1-IDDM,and uveitis; and (3) neurodegenerative diseases such as, for example,amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease,and primary lateral sclerosis. The method of the present invention isparticularly useful in the treatment of autoimmune diseases, preferablyas a therapy for treating MS and type-1-IDDM.

In a preferred embodiment, the present invention comprises a method forinhibiting a cellular process or activity mediated by IL-12, the methodcomprising:

(a) contacting IL-12 responsive cells with a compound of the presentinvention, as described above; and

(b) determining that the cellular process or activity mediated by IL-12is inhibited.

Pharmaceutical Compositions and Dosage

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.

The compounds of the present invention can be administered by any meansthat produces contact of the active agent with the agent's site ofaction in the body of a mammal. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents readily determinable by the skilledartisan. They can be administered alone, but are generally administeredwith a pharmaceutical carrier selected on the basis of the chosen routeof administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition. By wayof general guidance, the daily oral dosage of each active ingredient,when used for the indicated effects, will range between about 0.001 to1000 mg/kg of body weight, preferably between about 0.01 to about 100mg/kg of body weight per day, and most preferably between about 1.0 to20 mg/kg/day. Intravenously, the most preferred doses will range fromabout 1 to about 10 mg/kg/minute during a constant rate infusion.Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three, or four times daily.

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of skill in that art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

In the methods of the present invention, the inventive compounds canform the active ingredient, and are typically administered in admixturewith suitable pharmaceutical diluents, excipients, or carriers(collectively referred to herein as carrier materials) suitably selectedwith respect to the intended form of administration, that is, oraltablets, capsules, elixirs, syrups and the like, and consistent withconventional pharmaceutical practices. For instance, for oraladministration in the form of a tablet or capsule, the active drugcomponent can be combined with an oral, non-toxic, pharmaceuticallyacceptable, inert carrier such as lactose, starch, sucrose, glucose,methyl cellulose, magnesium stearate, dicalcium phosphate, calciumsulfate, mannitol, sorbitol and the like; for oral administration inliquid form, the oral drug components can be combined with any oral,non-toxic, pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents, and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include, without limitation, sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamallar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can include, withoutlimitation, polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol. Suitable pharmaceutical carriers are described inRemington's Pharmaceutical Sciences.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated, without limitation, as follows:

Capsules. A large number of unit capsules are prepared by fillingstandard two-piece hard gelatin capsules each with 100 milligrams ofpowdered active ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules. A mixture of active ingredient in a digestableoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into gelatin to formsoft gelatin capsules containing 100 milligrams of the activeingredient. The capsules are washed and dried.

Tablets. A large number of tablets are prepared by conventionalprocedures so that the dosage unit was 100 milligrams of activeingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams ofmagnesium stearate, 275 milligrams of microcrystalline cellulose, 11milligrams of starch and 98.8 milligrams of lactose. Appropriatecoatings may be applied to increase palatability or delay absorption.

Injectable. A parenteral composition suitable for administration byinjection is prepared by stirring 1.5% by weight of active ingredient in10% by volume propylene glycol and water. The solution is made isotonicwith sodium chloride and sterilized.

Suspension. An aqueous suspension is prepared for oral administration sothat each 5 mL contain 100 mg of finely divided active ingredient, 200mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

The compounds of the present invention may be administered incombination with a second therapeutic agent such as, for example, acorticosteroid, analgesics, etc. The compounds of the present inventionand such second therapeutic agent can be administered separately or as aphysical combination in a single dosage unit, in any dosage form and byvarious routes of administration, as described above. The compounds ofthe present invention may be formulated together with the secondtherapeutic agent in a single dosage unit (that is, combined together inone capsule, tablet, powder, or liquid, etc.). When the compounds of thepresent invention and the second therapeutic agent are not formulatedtogether in a single dosage unit, they may be administered essentiallyat the same time, or in any order; for example, the compounds of thepresent invention may be administered first, followed by administrationof the second agent. When not administered at the same time, preferablythe administration of a compound of the present invention and the secondtherapeutic agent occurs less than about one hour apart, more preferablyless than about 5 to 30 minutes apart. Preferably the route ofadministration is oral. Although it is preferable that the inventivecompound and the second therapeutic agent are both administered by thesame route (that is, for example, both orally), if desired, they mayeach be administered by different routes and in different dosage forms(that is, for example, one component of the combination product may beadministered orally, and another component may be administeredintravenously).

The dosage when administered alone or in combination with a secondtherapeutic agent may vary depending upon various factors such as thepharmacodynamic characteristics of the particular agent and its mode androute of administration, the age, health and weight of the recipient,the nature and extent of the symptoms, the kind of concurrent treatment,the frequency of treatment, and the effect desired, as described above.The proper dosage of a compound of the present invention whenadministered in combination with the second therapeutic agent will bereadily ascertainable by a medical practitioner skilled in the art, oncearmed with the present disclosure.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease.Patients may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

Synthesis

Compounds of the present invention can be synthesized using the methodsdescribed in the Examples below, which are preferred, as well as bysynthetic methods known in the art of synthetic organic chemistry, orvariations thereon as readily appreciated and readily performable bythose skilled in the art. The various synthetic steps described hereinmay be performed in an alternate sequence or order to give the desiredcompounds. Moreover, the synthesis Examples described herein are notintended to comprise a comprehensive list of all means by which thecompounds described and claimed in this patent application may besynthesized.

For example, 1,3,7-trisubstituted xanthine-based compounds of thepresent invention may be synthesized from 1,3-disubstituted xanthinecompounds, 1,7-disubstituted xanthine compounds, or 3,7-disubstitutedxanthine compounds. The 1,3,7-trisubstituted xanthine compound may beprepared by treating a 1,3-disubstituted xanthine compound with anappropriate base in a suitable solvent to provide an anion whichundergoes a substitution reaction with a compound substituted with anappropriate leaving group. Suitable bases include, but are not limitedto, sodium hydride and potassium tert-butoxide. Suitable solventsinclude, but are not limited to, dimethylformamide, dimethylsulfoxideand tetrahydrofuran. Suitable leaving groups include, but are notlimited to, chloro, bromo, iodo, methanesulfonato,trifluoromethanesulfonato and p-toluenesulfonato.

Alternatively, 1,3,7-Trisubstituted xanthine compounds may besynthesized from 1,3-disubstituted xanthine compounds, 1,7-disubstitutedxanthine compounds, or 3,7-disubstituted xanthine compounds using socalled Mitsunobu reaction conditions. For example, 1,3,7-Trisubstitutedxanthine compounds may be prepared by treating a 1,3-disubstitutedxanthine compound with a compound substituted with an alcohol group. Thealcohol group is activated to undergo a substitution reaction aftertreatment with an appropriate phosphine compound and an appropriate azocompound in a suitable solvent. Suitable phosphine compounds include,but are not limited to, triphenylphosphine and tributylphosphine. Anappropriate azo compound includes, but is not limited to,diethylazodicarboxylate. A suitable solvent includes, but is not limitedto, tetrahydrofuran.

8-Alkylsulfanylxanthine compounds are synthesized from8-mercaptoxanthine compounds which undergoes a substitution reactionwith a compound substituted with an appropriate leaving group. Thesubstitution reaction is conducted in the presence or absence of anappropriate base in a suitable solvent. Appropriate leaving groupsinclude, but are not limited to, chloro, bromo, iodo, methanesulfonato,trifluoromethanesulfonato and p-toluenesulfonato. An appropriate baseincludes, but is not limited to, potassium carbonate. Suitable solventsinclude, but are not limited to, acetonitrile, dimethylformamide,dimethylsulfoxide and tetrahydrofuran.

8-Aminoxanthine compounds may be synthesized from xanthine compoundssubstituted on the 8-position with an appropriate leaving group in asubstitution reaction with a compound containing an amino group. Thesubstitution reaction is carried out in a suitable solvent. Appropriateleaving groups include, but are not limited to, chloro, bromo, iodo,methanesulfonato, trifluoromethanesulfonato and p-toluenesulfonato.Suitable solvents include, but are not limited, to dimethylformamide,dimethylsulfoxide and tetrahydrofuran.

8-Aminomethylxanthine compounds may be synthesized from 8-methylxanthinecompounds substituted on the 8-methyl substituent with an appropriateleaving group in a substitution reaction with a compound containing anamino group. The substitution reaction is conducted in a suitablesolvent. Appropriate leaving groups include, but are not limited to,chloro, bromo, iodo, methanesulfonato, trifluoromethanesulfonato andp-toluenesulfonato. Suitable solvents include, but are not limited to,dimethylformamide, dimethylsulfoxide and tetrahydrofuran.

As can be appreciated by the skilled artisan, the preferred syntheticschemes described above and in the Examples below are not intended tocomprise a comprehensive list of all means by which the compoundsdescribed and claimed herein may be synthesized. It should be understoodthat the specified materials and conditions are important in practicingthe invention but that unspecified materials and conditions are notexcluded so long as they do not prevent the benefits of the inventionfrom being realized. Other suitable methods and starting materials willbe evident to those having skill in the art. Additionally, the varioussynthetic steps described may be performed in an alternate sequence ororder to give the desired compounds.

EXAMPLES

The present invention will be further illustrated in the following,non-limiting Examples. The Examples are illustrative only and do notlimit the claimed invention regarding the materials, conditions, processparameters and the like recited herein.

Example 1 Synthesis of 1-(5-(N-Hydroxy)aminohexyl)-3,7-dimethylxanthine(CT7549)

Sodium cyanoborohydride (62.84 mg, 1 mmol) was added to a solution of1-(5-oximinohexyl)-3,7-dimethylxanthine (Klein, J. P.; Leigh, A. OximeSubstituted Therapeutic Compounds, U.S. Pat. No. 5,770,595 (Jun. 23,1998)) (293 mg, 1 mmol) in methanol (10 ml). 1 M hydrogen chloride inether was added to pH 4-5. After stirring for 3 hours, the mixture wasconcentrated under reduced pressure. 1 N aqueous sodium hydroxidesolution to pH 9-10 (10 ml). The mixture was extracted with 10%methanol-dichloromethane (3×50 ml). The combined extracts were washedwith water (50 ml), dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with 10% methanol-dichloromethaneto provide 1-(5-(N-hydroxy)aminohexyl)-3,7-dimethylxanthine (180 mg).

Example 2 Synthesis of (R)-3-(5-Hydroxyhexyl)-1,7-dimethylxanthine(CT11495)

To a stirring solution of 1,7-dimethylxanthine (0.30 g, 1.67 mmol) indimethylsulfoxide (20 ml) was added sodium hydride (42 mmg, 1.75 mmol)in one portion. After stirring for 30 minutes,(R)-5-acetoxy-1-bromohexane (0.31 g, 1.75 mmol) was added neat.(R)-5-Acetoxy-1-bromohexane was prepared according to methods describedin U.S. patent application Ser. No. 09/002,345, which is incorporatedherein by reference. After heating at 80° C. for 18 hours, water (25 ml)was added and the aqueous solution was extracted with dichloromethane(3×20 ml). The combined extracts were washed with saturated aqueoussodium chloride solution (50 ml), dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica eluting with ethyl acetate to give(R)-3-(5-acetoxyhexyl)-1,7-dimethylxanthine (0.34 g, 64% yield) as acolorless oil.

To a stirring solution of (R)-3-(5-acetoxyhexyl)-1,7-dimethylxanthine(0.28 g, 0.87 mmol) in methanol (20 ml) was added an anhydrous solutionof hydrogen chloride in ethyl ether (1 M, 2.6 ml, 2.6 mmol). Afterrefluxing for 4 hours, the mixture was concentrated under reducedpressure. The residue was treated with saturated aqueous solution ofsodium bicarbonate solution (30 ml) and extracted with dichloromethane(3×20 ml). The combined extracts were washed with saturated aqueoussodium chloride solution (30 ml), dried over sodium sulfate andconcentrated under reduced pressure to give(R)-3-(5-hydroxyhexyl)-1,7-dimethylxanthine (0.20 g, 85% yield) as acolorless oil that solidified on standing.

Example 3 Synthesis of (R)-1-(5-Hydroxyhexyl)-3,7-dimethyluric acid(CT11499)

To a stirring solution of 3,7-dimethyluric acid (0.40 g, 2.04 mmol) indimethylsulfoxide (20 ml) was added sodium hydride (49 mg, 2.04 mmol) inone portion. After stirring for 45 minutes, a solution of chloromethylpivalate (0.29 g, 2.04 mmol) in dimethylsulfoxide (1 ml). After stirringfor 24 hours, water (50 ml) was added. After cooling to roomtemperature, the solid was filtered, rinsed with water (4×20 ml), withether (20 ml) and dried under vacuum to give9-pivaloyloxymethyl-3,7-dimethyluric acid (0.18 g, 28% yield) as a whitesolid.

To a stirring solution of 9-pivaloyloxymethyl-3,7-dimethyluric acid(0.14 g, 0.45 mmol) in dimethylsulfoxide (10 ml) was added sodiumhydride (12 mg, 0.47 mmol) in one portion. The solution was stirred for15 minutes. (R)-5-Acetoxy-1-iodohexane (0.13 g, 0.47 mmol) indimethylsulfoxide (1 ml) was added. The solution of(R)-5-acetoxy-1-iodohexane was prepared according to methods describedin U.S. patent application Ser. No. 09/002,345, which is incorporatedherein by reference. After stirring at room temperature for 24 hours,water (25 ml) was added and the aqueous solution was extracted withethyl acetate (3×15 ml). The combined extracts were washed withsaturated aqueous sodium chloride solution (15 ml), dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica eluting with ethyl acetate togive (R)-1-(5-acetoxyhexyl)-9-pivaloyloxymethyl-3,7-dimethyluric acid(0.10 g, 50% yield) as a white solid.

To a stirring solution of(R)-1-(5-acetoxyhexyl)-9-pivaloyloxymethyl-3,7-dimethyluric acid (0.10g, 0.22 mmol) in methanol (5 ml) was added solid sodium methoxide (48mg, 0.88 mmol) in one portion. After stirring at room temperature for 4days, the mixture was treated with 5% aqueous hydrochloric acid solution(0.25 ml) and concentrated under a stream of nitrogen and mild heating.The residue was purified by preparative thin layer chromatography (250micron silica gel plate) eluting with 7% methanol-dichloromethane toprovide (R)-1-(5-hydroxyhexyl)-3,7-dimethyluric acid (20 mg, 30% yield)as a white solid.

Example 4 Synthesis of(R)-1-(5-Hydroxyhexyl)-7-benzyl-3,8-dimethylxanthine (CT12407)

Glacial acetic acid (4.5 ml, 75 mmol) was added to a suspension of6-amino-1-methyluracil (5.66 g, 50 mmol) in hot water (100 ml). Sodiumnitrite (4.14 g) was added in portions and the reaction mixture wasstirred for 1 hour The precipitate was collected by filtration, washedwith water (75 ml) and then suspended in water (100 ml). The mixture waswarmed to 50° C. and sodium dithionite (10 g) was added in portionskeeping the temperature of the reaction between 50-55° C. The mixturewas stirred at 50° C. for 1 hr and then cooled to room temperature andfiltered. The solid was washed with water (2×25 ml), acetone (2×25 ml)and dried under vacuum to provide 5,6-diamino-1-methyluracil (5.6 g).

A solution of 5,6-diamino-1-methyluracil (2.5 g) in acetic anhydride (25ml) was heated at reflux for 2 hours and then the acetic anhydride wasevaporated under reduced pressure. The residue was dissolved in 10%aqueous sodium hydroxide solution (50 ml) and heated at reflux for 2hours. After cooling to room temperature, the mixture was acidified topH 4 by addition of concentrated hydrochloric acid. The precipitate wasfiltered, washed with water (15 ml), rinsed with acetone (15 ml) anddried under vacuum to provide 3,8-dimethylxanthine (1.8 g).

A solution of sodium hydroxide (400 mg) in water (5 ml) was added to asuspension of 3,8-dimethylxanthine (1.80 g) in methanol (10 ml). Afterstirring for 1 hour at 70° C., benzyl bromide (1.2 ml) was added. Afterstirring for 5 hours at 70-80° C., the solvent was evaporated underreduced pressure. The residue was treated with saturated aqueousammonium chloride solution (50 ml) and extracted with ethyl acetate(3×75 ml). The combined extracts were washed with saturated aqueoussodium chloride solution (30 ml), dried over magnesium sulfate andconcentrated under reduced pressure. The solid was purified byrecrystallization from ethanol to provide 7-benzyl-3,8-dimethylxanthine(1.06 g).

7-Benzyl-3,8-dimethylxanthine (500 mg, 1.85 mmol) was added to asuspension of sodium hydride (50.5 mg) in anhydrous dimethylsulfoxide(20 ml). After stirring for 30 minutes, (R) 5-acetoxy-1-chlorohexane(357 mg) was added and the mixture was warmed to 70-80° C. for 12 hours.The (R) 5-acetoxy-1-chlorohexane was prepared according to methodsdescribed in U.S. Pat. No. 5,629,423 issued to Klein, J. P., Leigh, A.J., Michnick, J., Kumar, A. M., Underiner, G. E., on May 13, 1997. Aftercooling to room temperature, the reaction was quenched by the additionof water (50 ml) and extracted with ethyl acetate (3×75 ml). Thecombined extracts were washed with water (2×50 ml), washed withsaturated aqueous sodium chloride solution (50 ml), dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel eluting with ethylacetate to give (R)-1-(5-acetoxyhexyl)-7-benzyl-3,8-dimethylxanthine(638 mg).

A solution of (R)-1-(5-Acetoxyhexyl)-7-benzyl-3,8-dimethylxanthine (500mg) in methanol (20 ml) was combined with hydrogen chloride in ether (1M, 2.5 ml) and stirred at room temperature for 12 hours. Afterevaporation of the solvent under reduced pressure, the residue wasdissolved in ethyl acetate (100 ml). The solution was washed withsaturated aqueous sodium bicarbonate solution (30 ml), dried overmagnesium sulfate and concentrated under reduced pressure to provide(R)-1-(5-hydroxyhexyl)-7-benzyl-3,8-dimethylxanthine (420 mg).

Example 5 Synthesis of(R)-3-(2-Furylmethyl)-1-(5-hydroxyhexyl)-7-methylxanthine (CT12422)

To a stirring solution of furfuryl alcohol (6.0 ml, 69.4 mmol) andcarbon tetrabromide (29.9 g, 90.2 mmol) in dichloromethane (70 ml) at 0°C. was added triphenylphosphine (23.7 g, 90.2 mmol) slowly over 30minutes (rapid addition results in polymerization of furfuryl moietiesas evidenced by a black-green solution). The reaction was stirred at 0°C. for an additional 30 minutes and then at room temperature for 1.5hours. Evaporation of the solvent under reduced pressure provided an oilthat was treated with hot hexane (150 ml). After cooling to roomtemperature the solid was filtered. The filtrate was treated withactivated charcoal (10 g), stirred for 1 hour and filtered through a padof celite. The filtrate was concentrated under reduced pressure. Theresidue was immediately distilled (43-46° C., 23 mm) with carefulexclusion of air to give furfuryl bromide (10.2 g, 91% yield) as acolorless oil which was used immediately in the next step.

To a stirring suspension of 7-methylxanthine (2.54 g, 15.3 mmol) indimethylsulfoxide (80 ml) was added sodium hydride (0.37 mg, 15.3 mmol)in one portion. After stirring for 30 minutes, freshly prepared furfurylbromide (2.5 g, 15.3 mmol) was added neat. After stirring at roomtemperature for 18 hours, the reaction was quenched by addition of water(150 ml). Saturated aqueous sodium chloride solution (30 ml) was addedand the mixture was extracted with chloroform (4×50 ml). The combinedextracts were washed with saturated aqueous sodium bicarbonate solution(3×50 ml), with saturated aqueous sodium chloride solution (2×50 ml) anddried over a mixture of sodium sulfate and activated charcoal. Afterfiltration through a pad of celite, the solvent was evaporated underreduced pressure. The residue was treated with ethyl acetate. The solidwas filtered, rinsed with cold ethyl acetate (2×25 ml) and vacuum driedto give 3-(2-furylmethyl)-7-methylxanthine (0.54 g, 14% yield) as abeige solid.

To a stirring suspension 3-(2-furylmethyl)-7-methylxanthine (0.40 g,1.62 mmol) in dimethylsulfoxide (20 ml) was added sodium hydride (41 mg,1.71 mmol) in one portion. After stirring for 25 minutes,(R)-5-acetoxy-1-iodohexane (0.46 g, 1.71 mol) was added neat. Afterstirring at room temperature for 72 hours, the reaction was quenched bythe addition of water (75 ml) and extracted with ethyl acetate (3×35ml). The combined extracts were washed with saturated aqueous sodiumchloride solution (2×35 ml), dried over sodium sulfate and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with ethyl acetate to give(R)-1-(5-acetoxyhexyl)-3-(2-furylmethyl)-7-methylxanthine (0.49 g, 78%yield) as a colorless oil.

To a stirring solution of(R)-1-(5-acetoxyhexyl)-3-(2-furylmethyl)-7-methylxanthine (0.42 g, 1.07mmol) in methanol (20 ml) was added a solution of hydrogen chloride in1,4-dioxane (4 M, 0.80 ml, 3.21 mmol) and the mixture was refluxed for 5hours. After cooling to room temperature, the solvent was evaporatedunder reduced pressure. The residue was treated with saturated aqueoussodium bicarbonate solution (25 ml) and the mixture was extracted withdichloromethane (3×25 ml). The combined extracts were washed withsaturated aqueous sodium chloride solution (2×25 ml), dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate to provide(R)-3-(2-furylmethyl)-1-(5-hydroxyhexyl)-7-methylxanthine (0.30 g, 80%yield).

Example 6 Synthesis of(R)-8-Aminomethyl-1-(5-hydroxyhexyl)-3-methylxanthine (CT12440)

To a stirring suspension of 3-methylxanthine (7.9 g 47.6 mmol) andsodium acetate (7.81 g, 95.2 mmol) in glacial acetic acid (120 ml) wasadded bromine (9.14 g, 57.1 mmol). The mixture was stirred at 65° C. for2 hours. After cooling to room temperature the precipitate was filtered,washed with acetic acid (2×15 ml), water (3×50 ml) and dried undervacuum to give 8-bromo-3-methylxanthine (10.5 g, 90% yield) as a beigepowder.

To a stirring suspension of 8-bromo-3-methylxanthine (7.06 g, 28.8 mmol)and potassium carbonate (3.98 g, 28.8 mmol) in DMF (150 ml) was addedchloromethyl ethyl ether (2.72 g, 28.8 mmol). After stirring overnightat room temperature, the reaction mixture was poured into ice-cold water(650 ml). After stirring at 0-5° C. for 1 hour, the cloudy mixture wasfiltered, washed with water (3×15 ml) and dried under vacuum to provide8-bromo-7-ethoxymethyl-3-methylxanthine (6.15 g, 70% yield) as a whitesolid.

To a stirring suspension of 8-bromo-7-ethoxymethyl-3-methylxanthine(1.52 g, 5.0 mmol) in anhydrous dimethylsulfoxide (20 ml) was addedsodium hydride (144 mg, 6.0 mmol). The mixture was stirred at roomtemperature for 30 min and then (R)-5-acetoxy-1-chlorohexane (983 mg,5.5 mmol) was added and the mixture was stirred at 70-750 C. After 12hours, the mixture was cooled to room temperature, quenched withsaturated aqueous sodium chloride solution (100 ml) and extracted withethyl acetate (3×50 ml). The combined extracts were washed with water(2×25 ml), with saturated aqueous sodium chloride solution (25 ml) anddried over magnesium sulfate. After evaporation of the solvent underreduced pressure, the product was purified by flash chromatography oversilica gel eluting with ethyl acetate to provide(R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (1.83 g,82% yield) as a beige solid.

To a solution of(R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (1.83 g,4.11 mmol) and sodium iodide (123 mg, 0.82 mmol) in anhydrousdimethylsulfoxide (40 ml) was added potassium cyanide (294 mg, 4.52mmol). After stirring at room temperature for 58 hours, the mixture wastreated with water (200 ml) and extracted with ethyl acetate (4×25 ml).The combined extracts were washed with saturated aqueous sodium chloridesolution (25 ml) and then dried over magnesium sulfate. After thesolvent was evaporated under reduced pressure, the product was purifiedby flash chromatography on silica gel eluting with ethyl acetate-hexane(1:3) to provide(R)-1-(5-Acetoxyhexyl)-8-cyano-7-ethoxymethyl-3-methylxanthine (970 mg,60% yield) as a pale yellow oil.

A suspension of(R)-1-(5-acetoxyhexyl)-8-cyano-7-ethoxymethyl-3-methylxanthine (750 mg,1.92 mmol) and 10% palladium on carbon (250 mg) in glacial acetic acid(40 ml) was treated with hydrogen gas (80 psi) on a Parr shaker for 3hours. The mixture was filter through a pad of celite and then thefiltrate was concentrated under reduced pressure to provide the aceticacid salt of(R)-1-(5-Acetoxyhexyl)-8-aminomethyl-7-ethoxymethyl-3-methylxanthine(800 mg, 91% yield) as a pale yellow oil.

To a stirring solution of(R)-1-(5-acetoxyhexyl)-8-aminomethyl-7-ethoxymethyl-3-methylxanthineacetic acid salt (300 mg, 0.66 mmol) in ethanol (20 ml) was added ananhydrous solution of hydrogen chloride in ethyl ether (1M, 2.0 ml, 2.0mmol). After heating at reflux overnight, the solvent was evaporatedunder reduced pressure to provide the product as a pale yellow oil.Hexane (5.0 ml) was added. After stirring for 1 hour, the resultingprecipitate was filtered to provide the hydrochloride salt of(R)-1-(5-hydroxyhexyl)-8-aminomethyl-3-methylxanthine (150 mg, 69%yield) as a white powder.

Example 7 Synthesis of(R)-1-(5-Hydroxyhexyl)-3methyl-8N-methyl)aminomethylxanthine (CT12441)

To a stirring suspension of 8-bromo-3-methylxanthine (prepared asdescribed for CT12440) (12.25 g, 50.0 mmol) and potassium carbonate(6.91 g, 50.0 mmol) in dimethylformamide (400 ml) was added benzylbromide (9.24 g, 54.0 mmol). After stirring for 12 hours, the mixturewas poured into cold water (680 ml). The precipitate was filtered,washed with water (3×50 ml), ether (3×50 ml) and dried under vacuum toprovide 7-benzyl-8-bromo-3-methylxanthine (14.92 g, 89% yield) as awhite powder.

To a stirring suspension of 7-benzyl-8-bromo-3-methylxanthine (10.06 g,30.0 mmol) in anhydrous dimethylsulfoxide was added sodium hydride (864mg, 36.0 mmol). After stirring at room temperature for 30 min,(R)-5-acetoxy-1-chlorohexane (5.9 g, 33.0 mmol) was added. Afterstirring at 70-75° C. for 12 hours, the mixture was cooled to roomtemperature, quenched with water (600 ml) and stirred at roomtemperature for 4 hours. The precipitate was filtered to provide(R)-1-(5-Acetoxyhexyl)-7-benzyl-8-bromo-3-methylxanthine (12.31 g, 86%yield) as a beige powder.

To a solution of(R)-1-(5-acetoxyhexyl)-7-benzyl-8-bromo-3-methylxanthine (9.55 g, 20.0mmol) in anhydrous dimethylsulfoxide was added potassium cyanide (1.43g, 22.0 mmol). After stirring at 70-80° C. for 4.5 hours, the mixturewas cooled to room temperature, quenched with water (500 ml) andextracted with ethyl acetate (4×150 ml). The combined extracts werewashed with saturated aqueous sodium chloride solution (45 ml), driedover magnesium sulfate and the solvent was evaporated under reducedpressure. The crude product was purified by flash chromatography onsilica gel eluting with ethyl acetate-hexane (1:1) to provide(R)-1-(5-acetoxyhexyl)-7-benzyl-8-cyano-3-methylxanthine (7.60 g, 90%yield) as a beige powder.

A suspension of (R)-1-(5-Acetoxyhexyl)-7-benzyl-8-cyano-3-methylxanthine(850 mg, 2.0 mmol) and 10% Pd on carbon (300 mg) in glacial acetic acid(60 ml) was treated with hydrogen gas (80 psi) on a Parr shaker for 3hours. After filtering through a pad of celite, the filtrate wasconcentrated under reduced pressure to provide the acetic acid salt of(R)-1-(5-acetoxyhexyl)-8-aminomethyl-7-benzyl-3-methylxanthine.

To a stirring solution of(R)-1-(5-acetoxyhexyl)-8-aminomethyl-7-benzyl-3-methylxanthine inchloroform (30 ml) was added trifluoroacetic anhydride (1.0 g, 4.76mmol). After stirring for 3 hours, the solvent was evaporated underreduced pressure. The crude product was purified by flash chromatographyon silica gel eluting with ethyl acetate to provide(R)-1-(5-acetoxyhexyl)-7-benzyl-8-N-trifluoroacetylaminomethyl-3-methyl-xanthine(1.0 g, 95% yield) as a white powder.

To the suspension of sodium hydride (36 mg, 1.5 mmol) in DMF (10 ml) wasadded(R)-1-(5-acetoxyhexyl)-7-benzyl-8-N-trifluoroacetylaminomethyl-3-methylxanthine(520 mg, 1.0 mmol). After stirring at room temperature for 30 minutes,methyl iodide (1.0 ml) was added. After stirring at room temperatureovernight, the mixture was poured into water (50 ml), extracted withethyl acetate (3×20 ml) and dried over magnesium sulfate. Evaporation ofthe solvent under reduced pressure provided(R)-1-(5-acetoxyhexyl)-7-benzyl-8-N-methyl-N-trifluoroacetylaminomethyl-3-methylxanthine.

A suspension of(R)-1-(5-acetoxyhexyl)-7-benzyl-8-N-methyl-N-trifluoroacetylaminomethyl-3-methylxanthineand 20% Pd(OH)₂ on carbon (300 mg) in glacial acetic acid (50 ml) wastreated with hydrogen gas (82 psi) on a Parr shaker for 24 hours. Afterfiltering through a pad of celite, the filtrate was concentrated underreduced pressure. The crude product was purified by flash chromatographyon silica gel eluting with ethyl acetate to provide(R)-1-(5-Acetoxyhexyl)-8-N-methyl-N-trifluoroacetylaminomethyl-3-methylxanthine(380 mg, 85% yield) as a white powder.

To a stirring solution of(R)-1-(5-acetoxyhexyl)-8-N-methyl-N-trifluoroacetylaminomethyl-3-methylxanthine(380 mg, 0.85 mmol) in methanol (30 ml) was added an anhydrous solutionof hydrogen chloride in ethyl ether (1 M, 2.0 ml, 2.0 mmol). Afterstirring at room temperature for 24 hours, the solvent was evaporatedunder reduced pressure. The resulting oil was treated with methanol(22.5 ml), water (2.25 ml) and potassium carbonate (900 mg, 5.0 mmol).After stirring at room temperature for 1 hour, the mixture was filteredand the filtrate was evaporated under reduced pressure. The crudeproduct was purified by flash chromatography on silica gel eluting withchloroform-methanol (1:1) to provide(R)-1-(5-hydroxyhexyl)-3-methyl-8-(N-methyl)aminomethylxanthine (170 mg,64% yield) as a colorless oil.

Example 8 Synthesis of(R)-1-(5-Hydroxyhexyl)-3-methyl-8-methylaminoxanthine (CT12447)

8-Bromo-7-ethoxymethyl-3-methylxanthine (prepared as described forCT12440) (3.03 g, 10 mmol) was added to a suspension of sodium hydride(264 mg, 11 mmol) in anhydrous dimethylsulfoxide (60 ml). After stirringfor 30 minutes, (R) 5-acetoxy-1-chlorohexane (1.963 g, 11 mmol) wasadded and the mixture was heated at 70-80° C. for 12 hours. Aftercooling to room temperature, the reaction was quenched by the additionof water (150 ml) and extracted with 10% methanol-ethyl acetate (3×25ml). The combined extracts were washed with water (2×50 ml), withsaturated aqueous sodium chloride solution (50 ml), dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting with 30% ethylacetate-hexane to provide(R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (2.77 g).

A 40% aqueous solution of methylamine (10 ml) was added to a solution of(R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (0.450 g)in dimethylsulfoxide (20 ml). After heating at 70° C. for 6 hours, themixture was treated with water (50 ml) and extracted with ethyl acetate(3×50 ml). The combined extracts were washed with water (2×30 ml), driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting with10% methanol-ethyl acetate to provide(R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-3-methyl-8-methylaminoxanthine(0.32 g).

A solution of(R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-3-methyl-8-methylaminoxanthine(0.32 g) in methanol (10 ml) was heated in presence of concentratedhydrochloric acid (2 drops) for 12 hours to 70° C. After evaporation ofthe solvent under reduced pressure, the residue was dissolved in 20%methanol-ethyl acetate (50 ml). The solution was washed with saturatedsodium bicarbonate solution (20 ml), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting with 10%methanol-ethyl acetate to provide(R)-1-(5-hydroxyhexyl)-3-methyl-8-methylaminoxanthine (0.100 g).

Example 9 Synthesis of (R)-1-(5-Hydroxyhexyl)-3-methyluric acid(CT12452)

To a stirring suspension of sodium hydride (5.52 g, 230 mmol) inanhydrous dimethylsulfoxide (500 ml) was added 6-amino-1-methyluracil(28.2 g, 200 mmol). After stirring at room temperature under argon for 2hours, (R)-5-Acetoxy-1-chlorohexane (37.5 g, 210 mmol) was added neatand the mixture was stirred at 80° C. for 16 hours. After cooling toroom temperature, the mixture was poured into saturated aqueous sodiumchloride solution (1500 ml) and extracted with ethyl acetate (9×200 ml).The combined extracts were washed with water (2×50 ml), with saturatedaqueous sodium chloride solution (50 ml) and dried over magnesiumsulfate. After evaporation of the solvent under reduced pressure, theresulting oil was treated with ethyl ether (400 ml). After stirringovernight at room temperature, the precipitate was filtered and rinsedwith ether (2×50 ml) to provide(R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (44.0 g, 78% yield) as abeige powder.

To the stirring solution of(R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (1.13 g, 4.0 mmol) inglacial acetic acid (22.5 ml) and water (7.5 ml) at 65° C. was addedsodium nitrite (345 mg, 5.0 mmol) in portions. The pink mixture wasstirred at 65° C. for 1 hour and then cooled to 0-5° C. Afterfiltration, the violet solid was washed with water (2×10 ml) and thensuspended in water (20 ml) and heated at 65° C. while sodiumhydrosulfite (2.78 g, 16.0 mmol) was added in portions. The pale yellowsolution was stirred at 65° C. for an additional 1 hour, cooled to roomtemperature and extracted with chloroform (3×25 ml). The combinedextracts were dried over magnesium sulfate and filtered to provide crude(R)-3-(5-acetoxyhexyl)-5,6-diamino-1-methyluracil in chloroform. To thisclear solution was added 1,1′-carbonyldiimidazole (650 mg, 4.0 mmol).After stirring overnight at room temperature, the mixture was washedwith water (2×25 ml), with 1 N aqueous hydrochloric acid (2×25 ml), withwater (2×25 ml), with saturated aqueous sodium chloride solution (25 ml)and then dried over magnesium sulfate. Evaporation of the solvent underreduced pressure provided the crude product which was purified by flashchromatography on silica gel eluting with ethyl acetate to provide(R)-1-(5-acetoxyhexyl)-3-methyluric acid (280 mg) as a beige solid whichwas dissolved in 20 ml of ethanol. To this solution was added hydrogenchloride in ethyl ether (1 M, 2.0 ml, 2.0 mmol). After refluxingovernight, the solvent was evaporated under reduced pressure. The crudeproduct was purified by flash chromatography on silica gel eluting withethyl acetate-methanol (7:1) to provide(R)-1-(5-hydroxyhexyl)-3-methyluric acid (210 mg, 19% yield) as a beigesolid.

Example 10 Synthesis of(R)-3-(5-Hydroxyhexyl)-1,7,9-trimethyl-2,4-pyrrolo[2,3d]pyrimidinedione(CT12458)

To a stirring solution of sulfuryl chloride in dichloromethane (1 M, 100ml) was added propionaldehyde (7 ml, 97 mmol) over 30 seconds. Afterstirring for 1 hour, methanol (24 ml) was added over 5 minutes. Vigorousgas evolution and refluxing was observed during this addition. Afterstirring at room temperature for 150 minutes, dichloromethane (75 ml)was removed by distillation. The remaining mixture was treated withsaturated aqueous sodium bicarbonate solution (100 ml). The mixture wasextracted with ether (100 ml). The extract was dried over magnesiumsulfate and concentrated under vacuum to provide 2-chloropropionaldehydedimethyl acetal (3.7 g, 27% yield).

To a mixture of water (3 ml), tetrahydrofuran (3 ml) and2-chloropropionaldehyde dimethyl acetal (1.46 g, 10.5 mmol) was addedconcentrated hydrochloric acid (0.2 ml) and stirred at 80-90° C. for 25minutes. After cooling to room temperature, sodium acetate (800 mg) wasdissolved in the aqueous phase. An aliquot (1 ml) of the upper organicphase was transferred to a stirring mixture of(R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (prepared as describedabove for CT12452) (365 mg, 1.29 mmol), sodium acetate (500 mg) andwater (6.5 ml) heated at 85° C. The mixture was heated at 85° C. for 40minutes. After cooling to room temperature, the mixture was extractedwith dichloromethane (2×15 ml). The combined extracts were dried overmagnesium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate to provide(R)-3-(5-acetoxyhexyl)-1,9-dimethyl-2,4-pyrrolo[2,3-d]pyrimidinedione(180 mg, 43% yield) as a pink solid.

A mixture of(R)-3-(5-acetoxyhexyl)-1,9-dimethyl-2,4-pyrrolo[2,3-d]pyrimidinedione(80 mg, 0.25 mmol), sodium hydride (15 mg, 0.62 mmol) and anhydrousdimethylsulfoxide (2 ml) was stirred for 3 minutes and then methyliodide (31 ul, 0.5 mmol) was added. After stirring for 2 hours, thereaction was quenched by addition of water (10 ml). The mixture wasextracted with dichloromethane (3×15 ml). The combined extracts weredried over magnesium sulfate and concentrated under vacuum to provide(R)-3-(5-acetoxyhexyl)-1,7,9-trimethyl-2,4-pyrrolo[2,3-d]pyrimidinedione(80 mg).

To a solution of(R)-3-(5-acetoxyhexyl)-1,7,9-trimethyl-2,4-pyrrolo[2,3-d]pyrimidinedione(80 mg) in methanol (3 ml) was added hydrogen chloride in ether (1 M,0.5 ml). After stirring at room temperature for 18 hours, the solutionwas treated with saturated aqueous sodium bicarbonate-sodium chloridesolution (10 ml) and extracted with dichloromethane (3×10 ml). Thecombined extracts were dried over magnesium sulfate and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel eluting with 3% methanol-ethyl acetate to provide(R)-3-(5-hydroxyhexyl)-1,7,9-trimethyl-2,4-pyrrolo[2,3-d]pyrimidinedione(46 mg, 65% yield) as a white powder.

Example 11 Synthesis of(R)-1,9-dimethyl-3-(5-hydroxyhexyl)-2,4-pyrrolo[2,3-d]pyrimidinedione(CT12459)

To a stirring solution of sulfuryl chloride in dichloromethane (1 M, 100ml) was added propionaldehyde (7 ml, 97 mmol) over 30 seconds. Afterstirring for 1 hour, methanol (24 ml) was added over 5 minutes. Vigorousgas evolution and refluxing was observed during this addition. Afterstirring at room temperature for 150 minutes, dichloromethane (75 ml)was removed by distillation. The remaining mixture was treated withsaturated aqueous sodium bicarbonate solution (100 ml). The mixture wasextracted with ether (100 ml). The extract was dried over magnesiumsulfate and concentrated under vacuum to provide 2-chloropropionaldehydedimethyl acetal (3.7 g, 27% yield).

To a mixture of water (3 ml), tetrahydrofuran (3 ml) and2-chloropropionaldehyde dimethyl acetal (1.46 g, 10.5 mmol) was addedconcentrated hydrochloric acid (0.2 ml) and stirred at 80-90° C. for 25minutes. After cooling to room temperature, sodium acetate (800 mg) wasdissolved in the aqueous phase. An aliquot (1 ml) of the upper organicphase was transferred to a stirring mixture of(R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (prepared as described forCT12452) (365 mg, 1.29 mmol), sodium acetate (500 mg) and water (6.5 ml)heated at 85° C. The mixture was heated at 85° C. for 40 minutes. Aftercooling to room temperature, the mixture was extracted withdichloromethane (2×15 ml). The combined extracts were dried overmagnesium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate to provide(R)-3-(5-acetoxyhexyl)-1,9-dimethyl-2,4-pyrrolo[2,3-d]pyrimidinedione(180 mg, 43% yield) as a pink solid.

To a solution of(R)-3-(5-acetoxyhexyl)-1,9-dimethyl-2,4-pyrrolo[2,3-d]pyrimidinedione(90 mg, 0.28 mmol) in methanol (3 ml) was added hydrogen chloride inether (1 M, 0.5 ml). After stirring at room temperature for 18 hours,the solution was treated with saturated aqueous sodiumbicarbonate-sodium chloride solution (10 ml) and extracted withdichloromethane (3×10 ml). The combined extracts were dried overmagnesium sulfate and concentrated under vacuum. The residue waspurified by flash chromatography on silica gel eluting with 5%methanol-dichloromethane to provide(R)-1,9-dimethyl-3-(5-hydroxyhexyl)-2,4-pyrrolo[2,3-d]pyrimidinedione(50 mg, 64% yield) as a white solid.

Example 12 Synthesis of(R)-3-(5-Hydroxyhexyl)-1-methyl-[1,2,5]thiadiazolo[3,4]pyrimidine-2,4-dione(CT12461)

To a stirring suspension of 5,6-diamino-1-methyluracil (718 mg, 4.6mmol) (which was prepared as described above for CT12407) and pyridine(3.0 ml) in acetonitrile (10 ml) was added thionyl chloride in oneportion. The reaction mixture was stirred at 70° C. for 15 min. Aftercooling to room temperature, the mixture was poured into 1 N aqueous HClsolution (80 ml) and extracted with ethyl acetate (5×15 ml). Thecombined extracts were washed with saturated aqueous sodium chloridesolution (15 ml) and dried over magnesium sulfate. Evaporation of thesolvent under reduced pressure provided1-methyl-[1,2,5]thiadiazolo[3,4-d]pyrimidine-2,4-dione (480 mg, 57%yield) as a light brown solid.

To a stirring suspension of1-methyl-[1,2,5]thiadiazolo[3,4-d]pyrimidine-2,4-dione (184 mg, 1.0mmol) and potassium carbonate (173 mg, 1.25 mmol) in DMF (7.5 ml) wasadded (R)-5-acetoxhexyl-1-chlorohexane (205 mg, 1.15 mmol) and stirredat 80° C. for 18 hours. After cooling to room temperature, the reactionmixture was quenched by the addition of saturated aqueous sodiumchloride solution (15 ml) and the mixture was extracted with ethylacetate (3×8 ml). The combined extracts were washed with water (5 ml),with saturated aqueous sodium chloride solution (5 ml) and dried overmagnesium sulfate. After evaporation of the solvent under reducedpressure, the crude product was purified by flash chromatography onsilica gel eluting with ethyl acetate-hexane (1:1) to provide(R)-3-(5-acetoxyhexyl)-1-methyl-[1,2,5]thiadiazolo[3,4]pyrimidine-2,4-dione(120 mg, 37% yield) as an oil.

To a stirring solution of(R)-3-(5-acetoxyhexyl)-1-methyl-[1,2,5]thiadiazolo[3,4]pyrimidine-2,4-dione(60 mg, 0.184 mmol) in methanol was added an anhydrous solution ofhydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol) and the mixturewas stirred at room temperature for 24 hours. After evaporation of thesolvent under reduced pressure, the crude product was purified by flashchromatography on silica gel eluting with ethyl acetate to provide(R)-3-(5-hydroxyhexyl)-1-methyl-[1,2,5]thiadiazolo[3,4]pyrimidine-2,4-dione(CT12461) (38 mg, 73% yield) as an oil.

Example 13 Synthesis of (R)-1-(5-Hydroxyhexyl)-3-methyl-8-azaxanthine(CT12463)

To the stirring solution of(R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (prepared as describedabove for CT12452) (567 mg, 2.0 mmol) in glacial acetic acid (12.5 ml)and water (2.5 ml) at 65° C. was added sodium nitrite (276 mg, 4.0 mmol)in portions. After stirring at 65° C. for 1 hour, the mixture was cooledto 0-5° and the precipitate was filtered. The violet solid was washedwith water (2×10 ml) and then suspended in water (20 ml). The mixturewas heated at 65° C. while sodium hydrosulfite was added in portions.After stirring at 65° C. for additional 20 minutes, the solution wastreated with glacial acetic acid (15 ml) followed by sodium nitrite (828mg, 12.0 mmol) in portions. After stirring at 65° C. for an additional25 min the mixture was cooled to room temperature and then extractedwith ethyl acetate (3×25 ml). The combined extracts were washed withsaturated aqueous sodium chloride solution (15 ml) and dried overmagnesium sulfate. Evaporation of the solvent under reduced pressureprovided (R)-1-(5-Acetoxyhexyl)-3-methyl-8-azaxanthine (400 mg, 65%yield) as an oil.

To a stirring solution of (R)-1-(5-acetoxyhexyl)-3-methyl-8-azaxanthine(150 mg, 0.49 mmol) in methanol (25 ml) was added an anhydrous solutionof hydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol). Afterstirring at room temperature for 24 hours, the solvent was evaporatedunder reduced pressure. The crude product was purified by flashchromatography on silica gel eluting with ethyl acetate-methanol (7:1)to provide (R)-1-(5-hydroxyhexyl)-3-methyl-8-azaxanthine (CT12463) (70mg, 54 mmol) as a white solid.

Example 14 Synthesis of(R)-3,7-Dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT12464) and(R)-3,8-Dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT12465)

To a suspension of sodium hydride (22 mg, 0.91 mmol) in anhydrousdimethylsulfoxide (4.0 ml) was added(R)-1-(5-acetoxyhexyl)-3-methyl-8-azaxanthine (225 mg, 0.728 mmol).After stirring at room temperature for 30 min, the mixture was treatedwith methyl iodide (524 mg, 3.64 mmol). After stirring at roomtemperature overnight, the reaction was quenched by addition ofsaturated aqueous sodium chloride solution (20 ml) and then extractedwith ethyl acetate (3×15 ml). The combined extracts were washed withwater (10 ml), with saturated aqueous sodium chloride solution (10 ml)and dried over magnesium sulfate. TLC showed that there were twoproducts in this mixture. After evaporation of the solvent under reducedpressure, the crude products were purified by flash chromatography onsilica gel eluting with ethyl acetate-hexane (1:1) to provide(R)-1-(5-acetoxyhexyl)-3,7-dimethyl-8-azaxanthine (74 mg, 31% yield)followed by (R)-1-(5-acetoxyhexyl)-3,8-dimethyl-8-azaxanthine (66 mg,28% yield).

To a solution of (R)-1-(5-acetoxyhexyl)-3,7-dimethyl-8-azaxanthine (71mg, 0.22 mmol) in methanol (15 ml) was added an anhydrous solution ofhydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol). The mixturewas stirred at room temperature for 24 hours and then the solvent wasevaporated under reduced pressure. The crude product was purified byflash chromatography on silica gel eluting with ethyl acetate-methanol(7:1) to provide (R)-3,7-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine(CT12464) (55 mg, 88% yield) as a white solid.

To a solution of (R)-1-(5-acetoxyhexyl)-3,8-dimethyl-8-azaxanthine (66mg, 0.204 mmol) in methanol (15 ml) was added an anhydrous solution ofhydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol). The mixturewas stirred at room temperature for 24 hours and then the solvent wasevaporated under reduced pressure. The crude product was purified byflash chromatography on silica gel eluting with ethyl acetate-methanol(7:1) to provide (R)-3,8-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (37mg, 65% yield) as a white solid.

Example 15 Synthesis of(R)-3,7-Dimethyl-1-(5-hydroxyhexyl)-8-N-methylaminoxanthine (CT12481)

To a stirring suspension of 8-bromo-3-methylxanthine (prepared asdescribed above for CT12440) (12.25 g, 50.0 mmol) and potassiumcarbonate (8.62 g, 62.5 mmol) in dimethylformamide (150 ml) was addedmethyl iodide (7.81 g, 55.0 mmol). After stirring overnight at roomtemperature, the mixture was poured into ice cold water (400 ml) andstirred at 0-5° C. for 1 hour. The precipitate was filtered, rinsed withwater (5×25 ml) and dried under vacuum to provide8-bromo-3,7-dimethylxanthine (12.10 g, 93% yield) as a beige solid.

To a stirring suspension of sodium hydride (740 mg, 30.8 mmol) inanhydrous dimethylsulfoxide (120 ml) was added8-bromo-3,7-dimethylxanthine (6.5 g, 25.0 mmol). After stirring at roomtemperature under argon for 1.5 hours, (R)-5-acetoxyhexyl-1-chlorohexane(4.91 g, 27.5 mmol) was added and the mixture was stirred at 80° C. for18 hours. After cooling to room temperature, the reaction mixture wasquenched by addition of saturated aqueous sodium chloride solution (300ml) and extracted with ethyl acetate (3×50 ml). The combined extractswere washed with water (2×20 ml), with saturated aqueous sodium chloridesolution (20 ml) and dried over magnesium sulfate. After evaporation ofthe solvent under reduced pressure, the crude product was purified byflash chromatography on silica gel eluting with ethyl acetate-hexane(1:1) to provide (R)-1-(5-acetoxyhexyl)-8-bromo-3,7-dimethylxanthine(7.38 g, 74% yield) as a colorless oil.

To a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-3,7-dimethylxanthine(5.88 g, 14.7 mmol) in methanol (200 ml) was added a solution ofhydrogen chloride in ether (1.0 M, 20 ml). The reaction mixture wasstirred at room temperature for 24 hours. Evaporation of the solventunder reduced pressure provided(R)-8-bromo-3,7-dimethyl-1-(5-hydroxyhexyl)xanthine (4.8 g, 91% yield)as a white solid. (R)-8-Bromo-3,7-dimethyl-1-(5-hydroxyhexyl)xanthine(359 mg, 1.0 mmol) was combined with a solution of methylamine in THF(2.0 M, 8.0 ml) and stirred at room temperature for 7 days. Afterevaporation of the solvent under reduced pressure, the crude product waspurified by flash chromatography on silica gel eluting with ethylacetate-methanol (4:1) to provide(R)-3,7-dimethyl-1-(5-hydroxyhexyl)-8-N-methylaminoxanthine (258 mg, 83%yield) as a white solid.

Example 16 Synthesis of(R)-3,7-Dimethyl-8-N,N-dimethylamino-1-(5-hydroxyhexyl)-xanthine(CT12485)

(R)-8-Bromo-3,7-dimethyl-1-(5-hydroxyhexyl)xanthine (prepared asdescribed above for CT12481) (180 mg, 0.50 mmol) was combined with asolution of dimethylamine in tetrahydrofuran (2.0 M, 10.0 ml) andstirred at room temperature for 3 days. After evaporation of the solventunder reduced pressure, the crude product was purified by flashchromatography on silica gel eluting with ethyl acetate-methanol (4:1)to provide(R)-3,7-dimethyl-8-N,N-dimethylamino-1-(5-hydroxyhexyl)-xanthine (78 mg,48% yield) as a white solid.

Example 17 Synthesis of(R)-1-(5-Hydroxyhexyl)-3-methyl-8-methylsulfanylxanthine (CT12490)

To a stirring solution of(R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (preparedas described above for CT12440) (1.77 g, 4.0 mmol) in ethanol (100 ml)was added sodium sulfide (4.48 g, 80 mmol). The reaction mixture wasstirred at 90° C. for 1 hour After evaporation of the solvent underreduced pressure, the crude product was purified by flash chromatographyon silica gel eluting with ethyl acetate-methanol (7:1) to provide(R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine. Thisproduct was dissolved in methanol (100 ml). A solution of hydrogenchloride in ether (1.0 M, 1.0 ml) was added and stirred at roomtemperature for 24 hours. After evaporation of the solvent under reducedpressure. The crude product was purified by flash chromatography onsilica gel eluting with ethyl acetate-methanol (4:1) to provide(R)-1-(5-hydroxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine (610mg, 51% yield) as a white solid.

To a stirring suspension of(R)-1-(5-hydroxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine (62.0mg, 0:174 mmol) and potassium carbonate (42 mg, 0.30 mmol) inacetonitrile (3.4 ml) was added methyl iodide (44 mg, 0.3 mmol). Thereaction mixture was stirred at room temperature for 3 hours. Afterevaporation of the solvent under reduced pressure. The crude product waspurified by flash chromatography on silica gel eluting with ethylacetate-hexane (3:1) to provide(R)-7-ethoxymethyl-1-(5-hydroxyhexyl)-3-methyl-8-methylsulfanylxanthine(58 mg, 89% yield) as a white solid.

To a solution of(R)-7-ethoxymethyl-1-(5-hydroxyhexyl)-3-methyl-8-methylsulfanylxanthine(20 mg, 0.054 mmol) in ethanol (1.9 ml) was added concentratedhydrochloric acid (0.10 ml). The reaction mixture was stirred at 80° C.for 24 hours. After evaporation of the solvent under reduced pressure,the crude product was purified by flash chromatography on silica geleluting with ethyl acetate-methanol (7:1) to provide(R)-1-(5-hydroxyhexyl)-3-methyl-8-methylsulfanylxanthine (12 mg, 70%yield) as a white solid.

Example 18 Synthesis of (S)-1-(5-Hydroxyhexyl)-7-benzyl-3-methylxanthine(CT22404)

A 10% aqueous sodium hydroxide solution (10 ml) was added to asuspension of 3-methylxanthine (4.15 g) in methanol (25 ml) and themixture was stirred for 1 hour at 70° C. Benzyl bromide (4.275 g, 2.97ml) was added dropwise at 70° C. and the mixture was stirred at 70-80°C. for an additional 5 hours. After cooling to room temperature, themixture was treated with water (50 ml). The precipitate was filtered,dissolved in 1 N aqueous sodium hydroxide solution (50 ml) and thesolution was acidified to pH 4-5 with concentrated hydrochloric acid.The precipitate was filtered and washed with water (3×20 ml) to provide7-benzyl-3-methylxanthine (4.45 g).

To a stirring suspension of 7-benzyl-3-methylxanthine (0.512 g, 2 mmol)in dimethyl sulfoxide (10 ml) was added 95% sodium hydride (50.5 mg, 2.0mmol) in one portion. After stirring for 30 minutes,(S)-5-acetoxy-1-bromohexane (0.490 g, 2.2 mmol) was added neat. Afterstirring at room temperature for 12 hours, the reaction was quenched byaddition of water (50 ml) and extracted with ethyl acetate (3×50 ml).The combined extracts were washed with saturated aqueous sodiumbicarbonate solution (50 ml), with saturated aqueous sodium chloridesolution (50 ml) and dried over magnesium sulfate. Evaporation of thesolvent under reduced pressure gave a residue which was purified byflash chromatography on silica gel eluting with ethyl acetate to give(S)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (0.700 g).

A solution of (S)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (350 mg)in methanol (10 ml) was treated with 1 M hydrogen chloride in ether (5ml). After stirring at room temperature for 12 hours, the solvent wasevaporated under reduced pressure. The residue was dissolved indichloromethane (100 ml). The solution was washed with saturated aqueoussodium bicarbonate solution (30 ml), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give(S)-1-(5-hydroxyhexyl)-7-benzyl-3-methylxanthine (270 mg).

Example 19 Synthesis of(S)-3,7-Dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT22464) and(S)-3,8-Dimethyl-1-5-hydroxyhexyl)-8-azaxanthine (CT22465)

(S)-3,7-Dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT22464) and(S)-3,8-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT22465) weresynthesized according to the methods described for(R)-3,7-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT12464) and for(R)-3,8-dimethyl-1-(5-hydroxyhexyl)-8-azaxanthine (CT12465) but using(S)-5-acetoxy-1-chlorohexane in place of (R)-5-acetoxy-1-chlorohexane.

Example 20 Synthesis of(R)-3-(N-biotinyl-6-aminohexyl)-1-5-hydroxyhexyl)-7-methylxanthine(CT12460)

a) N-t-BOC-6-amino-1-bromohexane was first prepared by addingdi-tert-butyldicarbonate (3.675 g, 16.4 mmol) to a solution of6-aminohexan-1-ol (1.6 g, 13.66 mmol) in 10% aqueous sodium hydroxidesolution (40 ml). After stirring for 4 hours, the mixture was treatedwith water (150 ml) and extracted with ethyl acetate (4×50 ml). Thecombined extracts were washed with water (2×50 ml), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by a flash chromatography on silica gel eluting with 20%methanol/dichloromethane to provide N-t-BOC-6-amino-hexan-1-ol (2.4 g).

A solution of bromine (1.60 g, 10 mmol) in dichloromethane (10 ml) wasadded to a solution of triphenyl phosphine (2.62 g, 10 mmol) andtriethylamine (1.01 g, 10 mmol) in dichloromethane (10 ml) at 0° C.After stirring at 0° C. for 30 minutes, a solution ofN-t-BOC-6-amino-hexan-1-ol (2.4 g) in dichloromethane (10 ml) was addeddropwise. After stirring for 2 hours, the mixture was concentrated underreduced pressure. The residue was purified by flash chromatographyeluting with 20% ethyl acetate/hexane to provideN-t-BOC-6-amino-1-bromohexane (2.5 g).

b) Then, (R)-1-(5-Acetoxyhexyl)-7-methylxanthine was prepared by heatinga mixture of N-benzylurea (100 g), cyanoacetic acid (62.37 g) and aceticanhydride (210 ml) at 70-80° C. for 2 hours. Upon cooling, crystals ofopen chain cyanoacetyl derivative began to precipitate. The mixture wasstirred with ether (500 ml) and then cooled in an ice-water bath for 2hours. The precipitate was filtered, washed with ether and dried in air.This solid was suspended in a mixture of water (200 ml) and ethanol (100ml). The mixture was heated at 85° C. while 10% aqueous sodium hydroxidesolution (50 ml) was gradually added. The cyanoacetyl derivativedissolved completely and a new solid precipitated gradually. The mixturewas heated at 85° C. for 30 minutes. After cooling to room temperature,the mixture was made slightly acidic by addition of concentratedhydrochloric acid solution. The precipitate was filtered, washed withwater and dried in air to provide 6-amino-1-benzyluracil (117 g).

6-Amino-1-benzyl-5-bromouracil. A solution of bromine (33.17 ml) inacetic acid (300 ml) was added slowly to a solution of6-amino-1-benzyluracil and anhydrous sodium acetate (93.29 g) in aceticacid (300 ml) and stirred for 6 hours. The reaction mixture was cooledin ice-cold water. The precipitate was filtered and dried under vacuumto provide 6-amino-1-benzyl-5-bromouracil (134.0 g).

6-Amino-1-benzyl-5-bromouracil (134 g) was stirred with 40% aqueousmethylamine solution (750 ml) for 24 hours. After cooling to 50° C., theprecipitate was filtered and dried under suction to provide6-amino-1-benzyl-5-methylaminouracil (55 g).

6-Amino-1-benzyl-5-methylaminouracil (11 g, 43 mmol) was added to asuspension of sodium hydride (1.032 mg, 43 mmol) in anhydrousdimethylsulfoxide (75 ml). After stirring for 30 minutes,(R)-5-acetoxy-1-chlorohexane (7.675 g, 43 mmol) was added. The mixturewas heated at 70-80° C. for 12 hours. After cooling to room temperature,the reaction was quenched by the addition of water (150 ml) andextracted with ethyl acetate (3×125 ml). The combined extracts werewashed with water (2×50 ml), with saturated aqueous sodium chloridesolution (50 ml), dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with ethyl acetate to provide(R)-3-(5-acetoxyhexyl)-6-amino-1-benzyl-5-methylaminouracil (7.89 g).

A mixture of (R)-3-(5-acetoxyhexyl)-6-amino-1-benzyl-5-methylaminouracil(7.89 g) and formic acid (200 ml) was heated at reflux for 1 hour Themixture was concentrated under reduced pressure to give crude(R)-3-(5-acetoxyhexyl)-6-amino-1-benzyl-5-N-methylformamidouracil thatwas used in the next step without further purification.

To a solution of(R)-3-(5-acetoxyhexyl)-6-amino-1-benzyl-5-N-methylformamidouracil,ethanol (125 ml), water (125 ml) and 30% aqueous ammonium hydroxidesolution (30 ml) was added 10% palladium on carbon (3.5 g) andhydrogenated at 70 psi for 12 hours. The mixture was filtered through apad of celite and the filtrate was concentrated under reduced pressureto provide (R)-3-(5-acetoxyhexyl)-6-amino-5-N-methylformamidouracil(7.19).

p-Toluenesulfonic acid (1 g) was added to a solution of(R)-3-(5-acetoxyhexyl)-6-amino-5-N-methylformamidouracil (7.1 g) informamide (150 ml) and the mixture was heated at reflux for 3 hours.After evaporation of the formamide, the residue was purified by flashchromatography on silica gel eluting with 10% methanol-dichloromethaneto provide (R)-1-(5-Acetoxyhexyl)-7-methylxanthine (3.8 g).

c) The (R)-1-(5-Acetoxyhexyl)-7-methylxanthine (1.285 g, 4.2 mmol) wasthen added to a suspension of sodium hydride (120 mg, 4.2 mmol) inanhydrous DMSO (15 ml). After stirring for 30 minutes, theN-t-BOC-6-amino-1-bromohexane (1.21 g, 4 mmol) was added and stirred.After stirring for 12 hours, the reaction was quenched by the additionof water (45 ml) and extracted with ethyl acetate (3×35 ml). Thecombined extracts were washed with water (2×25 ml), with saturatedaqueous sodium chloride solution (25 ml), dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting with ethylacetate to provide(R)-1-(5-acetoxyhexyl)-3-(N-tert-butyloxycarbonyl-6-aminohexyl)-7-methylxanthine(1.37 g).

Trifluoroacetic acid (30 ml) was added to a solution of(R)-1-(5-acetoxyhexyl)-3-(N-t-butyloxycarbonyl-6-aminohexyl)-7-methylxanthine(1.37 g) in dichloromethane (30 ml). After stirring at room temperaturefor 1 hour, the mixture was concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (50 ml). The solution waswashed with saturated aqueous sodium bicarbonate solution (20 ml), withwater (20 ml), with saturated aqueous sodium chloride solution (20 ml),dried over anhydrous magnesium sulfate and concentrated under reducedpressure to provide(R)-1-(5-acetoxyhexyl)-3-(6-aminohexyl)-7-methylxanthine (1.073 g).

Disopropylcarbodiimide (113.5 mg, 0.55 mmol) was added to a solution ofbiotin (122 mg, 0.5 mmol),(R)-1-(5-acetoxyhexyl)-3-(6-aminohexyl)-7-methylxanthine (227 mg, 0.5mmol) and 4-N,N-dimethylaminopyridine (73.3 mg, 0.6 mmol) indimethylformamide. After stirring at room temperature for 6 hours,dimethylformamide was evaporated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting with 20%methanol/ethyl acetate to provide(R)-1-(5-acetoxyhexyl)-3-(N-biotinyl-6-aminohexyl)-7-methylxanthine (110mg).

A solution of(R)-1-(5-acetoxyhexyl)-3-(N-biotinyl-6-aminohexyl)-7-methylxanthine (110mg) in methanol (10 ml) was treated with one drop of concentratedhydrochloric acid solution. After stirring at room temperature for 14hours, the mixture was treated with 2M solution of ammonia in methanol(3 ml) and concentrated under reduced pressure. The residue was purifiedby flash chromatography on silica gel eluting with 20%methanol/dichloromethane to provide(R)-3-(N-biotinyl-6-aminohexyl)-1-(5-hydroxyhexyl)-7-methylxanthine(CT12460) (66 mg).

Example 21 Synthesis of(R)-3-(N-biotinyl-2-aminoethyl)-1-(5-hydroxyhexyl)-7-methylxanthine(CT13410)

(R)-3-(N-Biotinyl-2-aminoethyl)-1-(5-hydroxyhexyl)-7-methylxanthine(CT13410) was prepared according to the method described above for(R)-3-(N-biotinyl-6-aminohexyl)-1-(5-hydroxyhexyl)-7-methylxanthine(CT12460) but using(R)-1-(5-acetoxyhexyl)-3-(2-aminoethyl)-7-methylxanthine in place of(R)-1-(5-acetoxyhexyl)-3-(6-aminohexyl)-7-methylxanthine. The(R)-1-(5-acetoxyhexyl)-3-(2-aminoethyl)-7-methylxanthine was preparedaccording to the following procedure.

Di-tert-butyldicarbonate (10.912 g, 50 mmol) was added to a solution ofethanolamine (3.054 g, 50 mmol) in 10% aqueous sodium hydroxide solution(40 ml) and stirred for 4 hours. The mixture was treated with water (150ml) and extracted with ethyl acetate (4×50 ml). The combined extractswere washed with water (2×50 ml), dried over magnesium sulfate andconcentrated under reduced pressure to provide N-t-BOC-ethanolamine (6.8g).

Triphenylphosphine (11.54 g) was added in portions to a solution ofcarbon tetrabromide (14.6 g) and N-t-BOC-ethanolamine (6.44 g) indichloromethane (300 ml). After stirring for 4 hours, the mixture wasconcentrated under reduced pressure to half its volume, diluted withhexane and filtered. The filtrate was concentrated under vacuum and theresidue was purified by flash chromatography on silica gel eluting withhexane to provide N-t-BOC-2-amino-1-bromoethane (4.6 g).

(R)-1-(5-Acetoxyhexyl)-7-methylxanthine (1.848 g, 6 mmol) (prepared asdescribed for CT12460) was added to a suspension of sodium hydride (144mg, 6 mmol) in anhydrous DMSO (15 ml). After stirring for 30 minutes,N-t-BOC-2-amino-1-bromoethane (1.344 g, 6 mmol) was added. Afterstirring for 12 hours, the reaction was quenched by the addition ofwater (45 ml) and extracted with ethyl acetate (3×35 ml). The combinedextracts were washed with water (2×25 ml), with saturated aqueous sodiumchloride solution (25 ml), dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with ethyl acetate to provide(R)-1-(5-acetoxyhexyl)-3-(N-t-BOC-2-aminoethyl)-7-methylxanthine (1.08g).

Trifluoroacetic acid (30 ml) was added to a solution of(R)-1-(5-acetoxyhexyl)-3-(N-t-BOC-2-aminoethyl)-7-methylxanthine (1.08g) in dichloromethane (30 ml). After stirring at room temperature for 1hour, the mixture was concentrated under reduced pressure. The residuewas dissolved in dichloromethane (50 ml). The solution was washed withsaturated aqueous sodium bicarbonate solution (20 ml), with water (20ml), with saturated aqueous sodium chloride solution (20 ml), dried overanhydrous magnesium sulfate and concentrated under reduced pressure toprovide (R)-1-(5-acetoxyhexyl)-3-(2-aminoethyl)-7-methylxanthine (0.72g).

Example 22 Synthesis of(R)-1-(5-N,N-Dimethylaminohexyl)-3,7-dimethylxanthine (CT11558)

A solution of (S)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine (Klein, J. P.;Leigh, A. J.; Michnick, J.; Kumar, A. M.; Underiner, G. E. AsymmetricSynthesis of Chiral Secondary Alcohols, U.S. Pat. No. 5,629,423 (May 13,1997)) (14 g, 50 mmol) and triethylamine (14 ml) was cooled to 0° C. indichloromethane (200 ml) and methanesulfonyl chloride (5.80 ml, 75 mmol)was added slowly at 0° C. After stirring for an additional 4 hours at 0°C., the reaction was quenched by the addition of water and extractedwith dichloromethane (4×150 ml). The combined extracts were washed withsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to provide(S)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (19.6 g).

Sodium azide (7.11 g, 0.1 mol) was added to a solution of(S)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (19.6 g, 54 mmol)in dimethylsulfoxide (100 ml) and stirred at 50° C. for 12 hours. Themixture was treated with water (200 ml) and extracted with ethyl acetate(3×100 ml). The combined extracts were washed with water (125 ml), withsaturated aqueous sodium chloride solution (150 ml), dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel eluting with ethylacetate to give (R)-1-(5-azidohexyl)-3,7-dimethylxanthine (13 g).

A solution of the (R)-1-(5-azidohexyl)-3,7-dimethylxanthine (620 mg) inethanol (25 ml) was hydrogenated at 70 psi of hydrogen gas in presenceof 10% palladium on carbon (150 mg) for 12 hours. After filtration toremove the catalyst, the filtrate was concentrated under reducedpressure to provide (R)-1-(5-aminohexyl)-3,7-dimethylxanthine.

A solution of sodium cyanoborohydride (75 mg) and zinc chloride (82 mg)in methanol (15 ml) was added to a solution of(R)-1-(5-aminohexyl)-3,7-dimethylxanthine (279 mg) and 37% aqueousformaldehyde (0.5 ml) in methanol (5 ml). After stirring for 2 hours,the reaction was quenched by addition of 0.1 N aqueous sodium hydroxidesolution (10 ml). After evaporation of most of the methanol underreduced pressure, the mixture was extracted with dichloromethane (5×40ml). The combined extracts were washed with water (50 ml), withsaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel eluting with 5%aqueous ammonium hydroxide, 35% methanol and 60% dichloromethane to give(R)-1-(5-N,N-dimethylaminohexyl)-3,7-dimethylxanthine (CT11558) (150mg).

Example 23 Synthesis of(S)-1-(5-N,N-Dimethylaminohexyl)-3,7-dimethylxanthine (CT21558).

(S)-1-(5-N,N-Dimethylaminohexyl)-3,7-dimethylxanthine (CT21558) wasprepared according to the method described for(R)-1-(5-N,N-dimethylaminohexyl)-3,7-dimethylxanthine (CT11558) butusing (R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine in place of(S)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine.

Example 24 Synthesis of (R)-1-(5-Acetamidohexyl)-3,7dimethylxanthine(CT12538).

Isobutylchloroformate (341 mg, 2.5 mmol) was added slowly to a solutionof acetic acid (146 mg, 2.5 mmol) and triethylamine (252.75 mg, 2.5mmol) in dichloromethane (20 ml) at −15° C. After warming to roomtemperature over 15 minutes, a solution of(R)-1-(5-aminohexyl)-3,7-dimethylxanthine (prepared as described forCT11558) (558 mg, 2 mmol) in dichloromethane (10 ml) was added. Afterstirring at room temperature for 12 hours, the mixture was concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with 13% methanol-ethyl acetate to provide(R)-1-(5-acetamidohexyl)-3,7-dimethylxanthine (CT12538) (380 mg).

Example 25 Synthesis of (R)-1-(5-Cyanohexyl)-3,7-dimethylxanthine(CT16575).

Potassium cyanide (280 mg, 4.30 mmol) was added to a solution of(S)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (prepared asdescribed for CT11558) (770 mg, 2.15 mmol) in dimethylsulfoxide (10 ml).After heating at 50° C. for 24 hours, the mixture was poured into water(50 ml) and extracted with ethyl acetate (3×50 ml). The combinedextracts were washed with water (40 ml), saturated aqueous sodiumchloride solution (40 ml), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate to provide(R)-1-(5-cyanohexyl)-3,7-dimethylxanthine

Example 26 Synthesis of(R)-8-Aminomethyl-1-(5-cyanohexyl)-3-methylxanthine (CT30289)

To a suspension of(S)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3-methylxanthine (prepared asdescribed for synthesis of(R)-1-(5-hydroxyhexyl)-8-aminomethyl-3,7-dimethylxanthine libraries)(10.5 g, 31 mmol) and potassium carbonate (8.6 g, 62 mmol) indimethylformamide (100 ml) was added benzyl bromide (6.67 g, 39 mmol).After stirring at room temperature overnight, the mixture was pouredinto ice water (250 ml) and stirred at 0-5° C. for 1 hour Theprecipitate was filtered, rinsed with water (4×50 ml) and dried undervacuum to provide(S)-1-(5-acetoxyhexyl)-7-benzyl-8-hydroxymethyl-3-methylxanthine (9.8 g,74% yield).

To a solution of thionyl chloride (100 ml) was added(S)-1-(5-acetoxyhexyl)-7-benzyl-8-hydroxymethyl-3-methylxanthine (9.8 g,22.9 mmol). After stirring for 3 hours at room temperature, unreactedthionyl chloride was evaporated under reduced pressure. The residual oilwas purified by flash chromatography on silica gel eluting with ethylacetate-hexane (1:1) to afford(S)-1-(5-acetoxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine (8.7 g,85% yield) as a colorless oil.

To a solution of(S)-1-(5-acetoxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine (8.7 g,19.5 mmol) was added a solution of hydrogen chloride in ether (1.0 M, 20ml). After stirring at room temperature for 24 hours, the solvent wasevaporated under reduced pressure to give(S)-1-(5-hydroxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine (7.0 g,89% yield) as a white solid.

A suspension of(S)-1-(5-hydroxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine (2.0 g,5.0 mmol) and sodium azide (1.62 g, 25 mmol) in methyl sulfoxide (15 ml)was stirred at 60° C. overnight. The reaction mixture was quenched byaddition of water (30 ml) and extracted with ethyl acetate (3×25 ml).The combined extracts were washed with water (2×10 ml), with saturatedaqueous sodium chloride solution (25 ml), dried over magnesium sulfate,and concentrated under reduced pressure. The crude product was purifiedby flash chromatography on silica gel eluting with ethyl acetate toprovide (S)-1-(5-hydroxyhexyl)-7-benzyl-8-azidomethyl-3-methylxanthine(1.7 g, 83% yield) as a colorless oil.

To a solution of(S)-1-(5-hydroxyhexyl)-7-benzyl-8-azidomethyl-3-methylxanthine (1.7 g,1.65 mmol) in ethanol (100 ml) was added 10% palladium on carboncatalyst (0.6 g). The mixture was treated with hydrogen gas (50 psi) ona Parr shaker for 18 hours. Removal of the catalyst by filtration andevaporation of the solvent under reduced pressure provided(S)-1-(5-hydroxyhexyl)-7-benzyl-8-aminomethyl-3-methylxanthine (1.6 g,100% yield).

To a solution of(S)-1-(5-hydroxyhexyl)-7-benzyl-8-aminomethyl-3-methylxanthine (1.6 g,4.1 mmol) was added triethylamine (1.26 g, 12.5 mmol) and di-tert-butyldicarbonate (1.63 g, 7.5 mmol). After stirring at room temperatureovernight, the solvent was evaporated under reduced pressure. The crudeproduct was purified by flash chromatography on silica gel eluting withethyl acetate to provide(S)-1-(5-hydroxyhexyl)-7-benzyl-8-(N-BOC-aminomethyl)-3-methylxanthine(1.5 g, 75% yield) as a white solid.

To a solution of(S)-1-(5-hydroxyhexyl)-7-benzyl-8-(N-BOC-aminomethyl)-3-methylxanthine(0.6 g, 1.24 mmol) in ethanol (60 ml) was added 10% palladium on carboncatalyst (0.5 g). The mixture was treated with hydrogen gas (50 psi) ona Parr shaker for 18 hours. Removal of the catalyst by filtration andevaporation of the solvent under reduced pressure provides(S)-1-(5-hydroxyhexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.4 g,82% yield) as a white solid.

To a solution of(S)-1-(5-hydroxyhexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.4 g,1.0 mmol) and 4-dimethylaminopyridine (0.61 g, 5.0 mmol) in chloroform(15 ml) was added methanesulfonic anhydride (0.35 g, 2.0 mmol). Afterstirring at room temperature overnight, the solvent was evaporated underreduced pressure. A mixture of ethyl acetate and water (1:1) (100 ml)was added. The organic phase was washed with aqueous potassium hydrogensulfate solution (0.1 N) to pH=2-3, with water (2×15 ml), with saturatedaqueous sodium chloride solution (15 ml), dried over magnesium sulfate,and concentrated under reduced pressure to afford(S)-1-(5-methanesulfonyloxyhexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine(0.47 g, 100% yield) as a white solid.

A suspension of(S)-1-(5-methanesulfonyloxyhexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine(0.47 g, 1.0 mmol) and potassium cyanide (0.39 g, 6.0 mmol) indimethylsulfoxide (8.0 ml) was stirred at 60° C. overnight. The reactionwas quenched by addition of water (30 ml) and extracted with ethylacetate (3×15 ml). The combined extracts were washed with water (2×15ml), saturated aqueous sodium chloride solution (15 ml), dried overmagnesium sulfate, and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography on silica gel eluting with15% methanol-ethyl acetate to give(R)-1-(5-cyanohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.25 g, 62%yield) as an oil.

To a 50% solution of trifluoroacetic acid in dichloromethane (15 ml) wasadded (R)-1-(5-cyanohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.21g, 0.52 mmol). After stirring at room temperature for 3 hours, thesolvent and excess reagent were evaporated under reduced pressure. Theresidue was treated with ammonia-methanol solution (2.0 M, 10 ml) andstirred for 1 hour After concentration under reduced pressure, the crudeproduct was purified by flash chromatography on silica gel eluting withammonium hydroxide (37% in water)-methanol-ethyl acetate mixture(1:10:5) to provide (R)-8-aminomethyl-1-(5-cyanohexyl)-3-methylxanthine(0.06 g, 38% yield) as a white solid.

Example 27 Synthesis of(R)-1-(5-Dimethylaminohexyl)-8-aminomethyl-3-methylxanthine (CT30280)

A suspension of the(S)-1-(5-methanesulfonyloxyhexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine(prepared as described for CT30289) (0.82 g, 1.80 mmol) and sodium azide(0.56 g, 8.6 mmol) in dimethylsulfoxide (5.0 ml) was stirred at 60° C.overnight. The reaction was quenched by addition of water (20 ml) andextracted with ethyl acetate (3×15 ml). The organic phase was washedwith water (2×15 ml), with saturated aqueous sodium chloride solution(15 ml), dried over magnesium sulfate, and concentrated under reducedpressure to afford(R)-1-(5-azidohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.7 g, 90%yield) as a white solid.

To a solution of(R)-1-(5-azidohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.7 g, 1.6mmol) in ethanol (40 ml) was added 10% palladium on carbon catalyst (0.3g). The mixture was treated with hydrogen gas (50 psi) on a Parr shakerfor 18 hours. Removal of the catalyst by filtration and evaporation ofthe solvent under reduced pressure provided(R)-1-(5-aminohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.5 g, 77%yield) as a white solid.

To a solution of(R)-1-(5-aminohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.4 g, 1.0mmol) in methanol (10 ml) was added formaldehyde (37% in water) (0.4 ml)followed by sodium cyanoborohydride (0.1 g, 1.5 mmol). After stirring atroom temperature for 1 hour, the solvent was evaporated under reducedpressure. The crude product was purified by flash chromatography onsilica gel eluting with ammonium hydroxide (37% in water)-methanol-ethylacetate mixture (1:5:10) to give(R)-1-(5-dimethylaminohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine(0.20 g, 47% yield) as an oil.

To a 50% solution of trifluoroacetic acid in dichloromethane (15 ml) wasadded(R)-1-(5-dimethylaminohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine(0.16 g, 0.38 mmol). After stirring at room temperature for 3 hours, thesolvent and excess reagent were evaporated under reduced pressure. Theresidue was treated with ammonia-methanol solution (2.0 M, 10 ml) andstirred for 1 hour Concentration under reduced pressure gave the crudeproduct which was purified by flash chromatography on silica gel elutingwith ammonium hydroxide (37% in water)-methanol-ethyl acetate (2:10:1).(R)-1-(5-Dimethylaminohexyl)-8-aminomethyl-3-methylxanthine (0.062 g,50% yield) was obtained as an oil.

Example 28 Synthesis of(R)-1-(5-Dimethylaminohexyl)-8-N-methylaminomethyl-3-methylxanthine (CT30274)

To a solution of(S)-1-(5-hydroxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine(prepared as described for the synthesis of CT 30289) (2.3 g, 5.68 mmol)in methanol (50 ml) was added methylamine (40% in water, 50 ml). Afterstirring at room temperature for 2 hours, the solvent and excess reagentwere evaporated under reduced pressure. A solution of triethylamine andethanol (1:4) (100 ml) was added and then evaporated under reducedpressure to give(S)-1-(5-hydroxyhexyl)-7-benzyl-8-methylaminomethyl-3-methylxanthine asa white powder.

To a solution of(S)-1-(5-hydroxyhexyl)-7-benzyl-8-methylaminomethyl-3-methylxanthine inmethanol (35 ml) was added triethylamine (1.44 g, 14.2 mmol) followed bydi-tert-butyl dicarbonate (1.85 g, 8.5 mmol). After stirring at roomtemperature overnight, the mixture was concentrated under reducedpressure. The residue was treated with water (50 ml) and extracted withethyl acetate (3×50 ml). The combined extracts were washed with water(2×25 ml), saturated aqueous sodium chloride solution (25 ml), driedover magnesium sulfate, and concentrated under reduced pressure. Thecrude product was purified by flash chromatography on silica gel elutingwith ethyl acetate-hexane (1:1) to provide(S)-1-(5-hydroxyhexyl)-7-benzyl-8-(N-BOC-methylaminomethyl)-3-methylxanthine(2.1 g, 76% yield) as a white solid.

(R)-1-(5-Dimethylaminohexyl)-8-N-methylaminomethyl-3-methylxanthine (CT30274) was synthesized from(S)-1-(5-hydroxyhexyl)-7-benzyl-8-(N-BOC-methylaminomethyl)-3-methylxanthineaccording to the method above for the synthesis of(R)-1-(5-dimethylaminohexyl)-8-aminomethyl-3-methylxanthine (CT30280)from(S)-1-(5-hydroxyhexyl)-7-benzyl-8-(N-BOC-aminomethyl)-3-methylxanthine.

Example 29 Synthesis of 7-substituted(R)-1-(5-hydroxyhexyl)-3-methylxanthine libraries

a) Brominated polystyrene was synthesized using a method described inFarrall, M. J., Frechet, M. J. J. Org. Chem., 1976, 41, 3877-82.Thallium trifluoroacetate (700 mg, 1.3 mmol) was added to a suspensionof polystyrene resin (10 g) in carbon tetrachloride (150 ml). Afterstirring in the dark for 30 minutes, a solution of bromine (6.8 g, 42mmol) in carbon tetrachloride (10 ml) was added slowly. After stirringat room temperature in the dark for 1 hour, the reaction mixture washeated to reflux for 90 minutes. Filtration followed by washing of thesolid with carbon tetrachloride, acetone, acetone-water (2:1), acetone,benzene and methanol (20 ml each) and drying under vacuum providedbrominated polystyrene (13.6 g).

b) Chlorosilylated polystyrene was synthesized using a method analogousto that described in Farrall, M. J., Frechet, M. J. J. Org. Chem., 1976,41, 3877-82. After stirring a suspension of brominated polystyrene (8 g)in anhydrous tetrahydrofuran (90 ml) for 30 minutes, a solution of 2.7 Mn-butyllithium in heptane (24 ml, 64 mmol). After stirring at 60° C. for3 hours, the reaction mixture was cooled to room temperature and thesupernant was removed by decantation. After cooling to −45° C.,anhydrous tetrahydrofuran (30 ml) was added followed bydichlorodiisopropylsilane (11.85 g, 64 mmol). The reaction mixture waswarmed to room temperature and shaken for 12 hours. Filtration followedby washing of the solid with dry tetrahydrofuran (30 ml) under positivepressure of argon and drying under vacuum afforded chlorosilylatedpolystyrene (9.24 g).

c) To a stirring suspension of 7-benzyl-3-methylxanthine (25.6 g, 100mmol) (which had been prepared as described for CT22404 of Example 18)in dimethylsulfoxide (200 ml) was added 95% sodium hydride (3.2 g, 133mmol) in portions over 10 minutes. After stirring for 30 minutes,(R)-5-acetoxy-1-chlorohexane (19.63 g, 110 mmol) was added neat. Afterheating at 70-80° C. for 6 hours, the reaction mixture was quenched byaddition of water (500 ml) and extracted with ethyl acetate (3×150 ml).The combined extracts were washed with water (150 ml), saturated aqueoussodium chloride solution (150 ml) and dried over magnesium sulfate.Evaporation of the solvent under reduced pressure gave a residue whichwas purified by flash chromatography on silica gel eluting with 20%hexane/ethyl acetate to give(R)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (33.7 g).

d) Potassium carbonate (30 g) was added to a solution of(R)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (33.7 g, 84.7 mmol) inmethanol (400 ml) and refluxed for 12 hours. After concentration underreduced pressure, the residue was partitioned between ethyl acetate (500ml) and water (300 ml). The organic layer was washed with water (100ml), dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to provide(R)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (27 g).

e) A mixture of (R)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (33.7g, 84.7 mmol), methanol (60 ml), acetic acid (60 ml), and 10% palladiumon carbon (6 g) was treated with hydrogen gas (40 psi) on a Parr shaker.After 14 hours, the mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with 10% methanol/ethyl acetate toprovide (R)-1-(5-hydroxyhexyl)-3-methylxanthine (15 g).

f) Chlorosilylated polystyrene (3.51 g) was shaken with a solution of(R)-1-(5-hydroxyhexyl)-3-methylxanthine (6.15 g, 23.1 mmol) andimidazole (2.1 g, 30.8 mmol) in dichloromethane-dimethylformamide (3:1)(40 ml) for 48 hours. Filtration followed by washing of the solid withdimethylformamide, dichloromethane and ethyl acetate (5×10 ml of each)and drying under vacuum provided resin loaded(R)-1-(5-hydroxyhexyl)-3-methylxanthine (4.556 g). The filtrate wasconcentrated under reduced pressure and the residue was purified byflash chromatography on silica gel eluting with 10% methanol/ethylacetate to recover unreacted (R)-1-(5-hydroxyhexyl)-3-methylxanthine(3.76 g).

g) Resin loaded (R)-1-(5-hydroxyhexyl)-3-methylxanthine (2 g) wassuspended in a solution of 1,2-dichloroethane-dimethylformamide (4:3,175 ml) so that a homogeneous suspension is formed. The homogeneoussuspension was evenly distributed to 80 wells (2.2 ml per well) of a96-well filter plate. The solvent was removed by filtration, the resinin each well was washed with dichloromethane (1.25 ml per well). Asolution of diethyl azodicarboxylate (4.38 g, 25 mmol) indichloromethane (25 ml) was added slowly to a solution oftriphenylphosphine (6.77 g, 25.8 mmol) in tetrahydrofuran (20 ml) at0-5° C. This solution was equally distributed to the 80 wells. 1 Msolutions of 80 different alcohols in tetrahydrofuran (0.27 ml per well,0.27 mmol) were added (one alcohol per well). The plate was sealed andshaken on an orbital shaker for 72 hours. After filtration, the resin ineach well was washed with dichloromethane (5×1 ml). The products werecleaved from the resin by treatment with a solution of trifluoroaceticacid-methanol-dichloroethane (2:1:1, 0.5 ml per well). After shaking for2 hours, filtration into a 96-well collection plate, washing of theresin with 20% methanol-dichloroethane (2×0.5 ml per well), andconcentration of the contents of the collection plate under reducedpressure provided a library of eighty 7-substituted(R)-1-(5-hydroxyhexyl)-3-methylxanthines. The purity of each product wasevaluated by thin-layer chromatography (TLC).

Example 30 Synthesis of 7-substitued(S)-1-(5-hydroxyhexyl)-3-methylxanthine libraries

a) Diethyl azodicarboxylate (14.63 g, 84 mmol) was added dropwise to asolution of (R)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (asprepared in Example 29) (20 g, 56 mmol), 4-nitrobenzoic acid (14 g, 84mmol) and triphenylphosphine (22 g, 84 mmol) in tetrahydrofuran (200ml). After stirring for 30 minutes, the reaction mixture wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with 30% ethyl acetate-hexane toprovide (S)-7-benzyl-1-(5-(4-nitrobenzoyloxy)hexyl)-3-methylxanthine (25g).

b) (S)-7-benzyl-1-(5-(4-nitrobenzoyloxy)hexyl)-3-methylxanthine (25 g,49.5 mmol) was added to a solution of sodium hydroxide (3.36 g, 84 mmol)in methanol (200 ml). After stirring for 2-hours, the pH was adjusted to4 by addition of 1 N hydrochloric acid solution. After concentratingunder reduced pressure, the residue was partitioned between water (150ml) and ethyl acetate (300 ml). The organic layer was washed withsaturated aqueous sodium chloride solution (150 ml), dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting with20% hexane-ethyl acetate to provide(S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (14 g).

c) A mixture of (S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (14 g,39 mmol), acetic acid (100 ml), methanol (50 ml), and 10% palladium oncarbon (5 g) was treated with hydrogen gas (40 psi) for 14 hours. Themixture was filtered and the filtrate was concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with 10% methanol-ethyl acetate to give(S)-1-(5-hydroxyhexyl)-3-methylxanthine (6.5 g).

d) 7-Substituted (S)-1-(5-hydroxyhexyl)-3-methylxanthine libraries weresynthesized from (S)-1-(5-hydroxyhexyl)-3-methylxanthine according tothe method described in Example 29 for the synthesis of 7-substituted(R)-1-(5-hydroxyhexyl)-3-methylxanthine libraries from(R)-1-(5-hydroxyhexyl)-3-methylxanthine.

Example 31 Synthesis of 3-substituted(R)-1-(5-hydroxyhexyl)-7-methylxanthine libraries

a) Potassium hydroxide (1.0 g, 17.8 mmol) was added to a solution of(R)-1-(5-acetoxyhexyl)-7-methylxanthine (prepared as described forCT12460) (3.8 g, 12.3 mmol) in methanol-water (1:1, 100 ml). Afterstirring for 3 hours, the pH of the solution was adjusted to 7 by theslow addition of 1 N hydrochloric acid. The solution was concentratedunder reduced pressure and the residue was purified by flashchromatography on silica gel eluting with 15% methanol-ethyl acetate toprovide (R)-1-(5-hydroxyhexyl)-7-methylxanthine (2.5 g).

b) 3-Substituted (R)-1-(5-hydroxyhexyl)-7-methylxanthine libraries weresynthesized from (R)-1-(5-hydroxyhexyl)-7-methylxanthine according tothe method described in Example 29 for the synthesis of 7-substituted(R)-1-(5-hydroxyhexyl)-3-methylxanthine libraries from(R)-1-(5-hydroxyhexyl)-3-methylxanthine.

Example 32 Synthesis of 3-substituted(S)-1-(5-hydroxyhexyl)-7-methylxanthine libraries

a) (S)-1-(5-hydroxyhexyl)-7-methylxanthine was synthesized from(R)-1-(5-hydroxyhexyl)-7-methylxanthine according to the methoddescribed in Example 30 for the synthesis of(S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine from(R)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine.

b) 3-Substituted (S)-1-(5-hydroxyhexyl)-7-methylxanthine libraries weresynthesized from (S)-1-(5-hydroxyhexyl)-7-methylxanthine according tothe method described in Example 30 for the synthesis of 7-substituted(S)-1-(5-hydroxyhexyl)-3-methylxanthine libraries from(S)-1-(5-hydroxyhexyl)-3-methylxanthine.

Example 33 Synthesis of(R)-1-(5-hydroxyhexyl)-7-ethoxymethyl8-amino-3-methylxanthine libraries

a) To a solution of(R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (preparedas described for CT12440) (3.8 g, 8.5 mmol) in methanol (150 ml) wasadded a solution of hydrogen chloride in ether (1.0 M, 20 ml). Thereaction mixture was stirred at room temperature for 24 hours.Evaporation of the solvent under reduced pressure provided(R)-1-(5-hydroxyhexyl)-8-bromo-3-methylxanthine (2.9 g, 98% yield) as awhite solid.

b) To a stirring suspension of(R)-1-(5-hydroxyhexyl)-8-bromo-3-methylxanthine (2.9 g, 8.4 mmol) andpotassium carbonate (1.50 g, 10.5 mmol) in dimethylformamide (70 ml) wasadded chloromethyl ethyl ether (0.83 g, 8.8 mmol). After stirringovernight at room temperature, the mixture was poured into ice coldwater (200 ml) and was stirred at 0-5° C. for 1 hour The precipitate wasfiltered, rinsed with water (5×25 ml) and dried under vacuum to provide(R)-1-(5-hydroxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (2.5 g,74% yield) as a white solid.

c) To a stirring solution of(R)-1-(5-hydroxyhexyl)-8-bromo-7-ethoxymetyl-3-methylxanthine (2.5 g,6.2 mmol), 4-dimethylaminopyridine (0.38 g, 3.3 mmol) and triethylamine(1.25 g, 12.4 mmol) in chloroform (40 ml) was added succinic anhydride(0.93 g, 9.3 mmol). After stirring overnight at room temperature, themixture was quenched with ice cold water (100 ml) and stirred at 0-5° C.for 1 hour Potassium hydrogensulfate solution (0.5 N) was added untilpH=2-3. The organic phase was separated and washed with saturatedaqueous sodium chloride solution (2×35 ml), dried over magnesium sulfateand concentrated under reduced pressure to provide(R)-1-(5-hydroxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthinemonosuccinate ester (3.0 g, 96% yield) as an oil.

d) To a suspension of(R)-1-(5-hydroxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthinemonosuccinate ester (3.0 g, 6.0 mmol), 4-dimethylaminopyridine (0.24 g,2.1 mmol) and Argo-Gel-NH₂ resin (5.0 g, 2.1 mmol) in chloroform (70 ml)was added 1,3-diisopropylcarbodiimide (0.76 g, 6.0 mmol). The reactionmixture was shaken at room temperature for 24 hours. After filtration,the resin was rinsed with chloroform (3×50 ml),chloroform-dimethylformamide (1:1, 3×50 ml), dimethylformamide (2×50ml), chloroform-dimethylformamide (1:1, 3×50 ml) and chloroform (4×50ml). After drying under reduced pressure, resin bound(R)-1-(5-hydroxyhexyl)-8bromo-7-ethoxymethyl-3-methylxanthine(succinate-linked) (6.0 g) was obtained.

e) Resin bound(R)-1-(5-hydroxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine(succinate-linked) obtained above was evenly distributed to 80 wells ofa 96-well teflon filter block (Charybdis). 80 different amines indimethylsulfoxide (10 equiv., 1.0 M) were added to the wells (1 perwell). The block was sealed and shaken in an incubator-shaker at 60° C.for 48 hours. After filtration, the resin in each well was rinsed withdimethylsulfoxide (3×0.25 ml), chloroform-dimethylformamide (1:1, 3×0.25ml), dimethylformamide (3×0.25 ml) and chloroform (3×0.25 ml). Productswere cleaved from the resin by addition of ammonia in methanol (2.0 M,0.65 ml per well). After shaking at room temperature for 48 hours, theresin in each well was filtered and the filtrates individually collectedin 80 wells of a 96-well collection plate. Evaporation under reducedpressure provided an(R)-1-(5-hydroxyhexyl)-7-ethoxymethyl-8-amino-3-methylxanthine library.

Example 34 Synthesis of (R)-1-(5-hydroxyhexyl)-8-amino-3-methylxanthinelibraries

(R)-1-(5-Hydroxyhexyl)-7-ethoxymethyl-8-amino-3-methylxanthine librariessynthesized as described in Example 33 were treated with a solutioncomposed of concentrated hydrochloric acid and ethanol (1:4, 0.8 ml perwell) and the block was heated in an oven at 80° C. for 12 hours.Remaining reagents and byproducts were evaporated under reduced pressureproviding (R)-1-(5-hydroxyhexyl)-8-amino-3-methylxanthine libraries.

Example 35 Synthesis of(R)-1-(5-hydroxyhexyl)-8-aminomethyl-3,7-dimethylxanthine libraries

a) To a stirred suspension of(R)-3-(5-acetoxyhexyl)-6-amino-1-methyl-5-nitroso-uracil (prepared asdescribed for CT12452) (23.35 g, 74.8 mmol) in water (230 ml) at 60° C.was added sodium hydrosulfite (61.7 g) in portions. After heating at 60°C. for additional 1 hour, the reaction mixture was cooled to 0-5° C.Chloroform (240 ml) was added followed by potassium carbonate (51.8 g,37.5 mmol) in portions. The reaction mixture was stirred at 0-5° C. foradditional 0.5 hour whereupon benzyloxyacetyl chloride (20.7 g, 112mmol) was added dropwise. After stirring at 0-5° C. for an additional 1hour, the mixture was extracted with 10% methanol-chloroform solution(1100 ml). The aqueous phase was further extracted with 10%methanol-chloroform solution (3×250 ml). The combined organic extractswere evaporated under reduced pressure to provide a beige solid whichwas dissolved in 10% aqueous sodium hydroxide solution (500 ml) andheated at reflux for 0.5 hour After cooling to 0-5° C., the pH wasadjusted to 2-3 by addition of concentrated hydrochloric acid and themixture was extracted with ethyl acetate (5×250 ml). The combinedextracts were washed with saturated aqueous sodium chloride solution(100 ml), dried over magnesium sulfate, and concentrated under reducedpressure to provide a crude product. Recrystallization (ethylacetate-hexane) provided(R)-8-benzyloxymethyl-1-(5-hydroxyhexyl)-3-methylxanthine (22.0 g, 77%yield) as a white solid.

b) To a stirred solution of(R)-8-benzyloxymethyl-1-(5-hydroxyhexyl)-3-methylxanthine (19.9 g, 51.5mmol), triethylamine (10.4 g, 103 mmol) and 4-dimethylaminopyridine(1.33 g, 11 mmol) in chloroform (130 ml) was added acetic anhydride(6.57 g, 64.4 mmol). After stirring for 3 hours at room temperature, thereaction mixture was quenched by addition of methanol (5 ml). Themixture was washed with aqueous potassium hydrogen sulfate solution (0.1N) to pH˜6-7, with water (2×50 ml) and with saturated aqueous sodiumchloride solution (50 ml). After drying over magnesium sulfate, theorganic solution was evaporated under reduced pressure to provide(R)-1-(5-acetoxyhexyl)-8-benzoxymethyl-3-methylxanthine (19.6 g, 88%yield) as white colored solid.

c) To a solution of(R)-1-(5-acetoxyhexyl)-8-benzoxymethyl-3-methylxanthine (4.0 g, 9.33mmol) in acetic acid (40 ml) was added 10% palladium on carbon (0.52 g).The mixture was treated with hydrogen gas (50 psi) on a Parr shaker for18 hours. After removing catalyst by filtration, evaporation of thesolvent under reduced pressure provided(R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3-methylxanthine (2.8 g, 88%yield) as a white solid.

d) To a stirred suspension of(R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3-methylxanthine (6.35 g, 18.8mmol) and potassium carbonate (5.2 g, 38 mmol) in dimethylformamide (55ml) was added methyl iodide (4.0 g, 28.2 mmol). After stirring overnightat room temperature, the mixture was poured into ice cold water (250 ml)and stirred at 0-5° C. for 1 hour The precipitate was filtered, rinsedwith water (5×25 ml), and dried under vacuum to provide(R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3,7-dimethylxanthine (6.3 g, 95%yield) as a white solid.

e) To thionyl chloride (30 ml) stirred at 0-5° C. was added(R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3,7-dimethylxanthine (6.3 g, 17.9mmol). After stirring overnight at room temperature, unreacted thionylchloride and volatile byproducts were evaporated under reduced pressure.To the residual oil was added methanol (300 ml) followed by hydrogenchloride in ether (1.0 M, 20 ml). After stirring for 12 hours, volatilematerials were evaporated under reduced pressure to provide(R)-1-(5-hydroxyhexyl)-8-chloromethyl-3,7-dimethylxanthine (5.6 g, 96%yield) as a white solid.

f) To a suspension of(R)-1-(5-hydroxyhexyl)-8-chloromethyl-3,7-dimethylxanthine (5.6 g, 17.0mmol) and 3,4-dihydro-2H-pyran-2-ylmethoxymethyl polystyrene (DHP HMresin, Novabiochem) (3.6 g, 3.4 mmol) in dichloroethane (55 ml) anddimethylsulfoxide (20 ml) was added p-toluenesulfonic acid (0.90 g, 3.4mmol). After shaking at 4° C. for 16 hours, the resin was filtered andrinsed with dimethylsulfoxide (3×50 ml),dichloromethane-dimethylsulfoxide (1:1) (3×50 ml), and dichloromethane(4×50 ml). Drying under reduced pressure provided resin bound(R)-1-(5-hydroxyhexyl)-8-chloromethyl-3,7-dimethylxanthine (4.65 g).g)Resin bound (R)-1-(5-hydroxyhexyl)-8-chloromethyl-3,7-dimethylxanthine(4.65 g) was distributed evenly to 80 wells of a 96-well teflon filterblock (Charybdis). Solutions of 80 different amines in tetrahydrofuran(10 equiv., 1.0 M) were added to the wells (1 per well). The block wassealed and shaken in an incubator-shaker at 50° C. for 18 hours. Afterfiltration, the resin in each well was rinsed with dimethylsulfoxide(5×0.6 ml), dichloromethane-dimethylsulfoxide (1:1, 10×0.6 ml), anddichloromethane (5×0.6 ml). Products were cleaved from the resin byaddition of a solution composed of hydrogen chloride (4.0 M in dioxide),ethanol, and dichloroethane and (2:1:1, 0.8 ml per well). The block wasshaken at room temperature for 18 hours. After filtration, the resin ineach well was filtered and the filtrates individually collected in 80wells of a 96-well collection plate. Evaporation under reduced pressureprovided an (R)-1-(5-hydroxyhexyl)-8-aminomethyl-3,7-dimethylxanthinelibrary.

Example 36 Effect on IL-12 Signaling

This example illustrates the inventive compounds' ability to suppressTh1 differentiation in vitro by blocking IL-12 signaling. Each ofcompounds A through Y were tested in an IL-12 dependent in vitroT-helper cell differentiation assay as described in LeGross et al., J.Exp. Med., 172:921-929 (1990). Recombinant IL-12 was used to induce Th1differentiation. Splenic T cells were purified utilizing the antibodiesRA3-3A1/6.1 (anti-B220), J11d and MAR18.5 (anti-rat kappa chain) todeplete the B cells via complement mediated toxicity following theprocedure set forth in Klaus et al., J. Immunol., 149:1867-1875 (1992).Splenic T cells were stimulated at 5×10⁵/ml with insoluble anti-CD3alone (145-2C11, Pharmingen, San Diego, Calif.), or anti-CD3 and 5 U/mlIL-12, with and without each inventive compound. After seven days, equalnumbers of viable cells were restimulated for 24 hours with anti-CD3without the inventive compounds, and the supernatants were collected andassayed for IFN-γ production. IFN-γ and IL-4 levels were measured byIntertest kits from Genzyme specific for IFN-γ and IL-4. The results areshown in Table 2 below.

Th1 differentiation was induced by culturing anti-CD3 stimulated T cellsin the presence of exogenous IL-12. Under these conditions, Th1differentiation was consistently enhanced as compared to T cellsstimulated with anti-CD3 alone. It was observed that the presence of thetested compounds during T cell activation inhibited Th1 differentiation,which had been enhanced by the addition of exogenous IL-12. The valuesin the “IC₅₀ μM” column were determined by measuring the inhibition ofIL-12 induced Th1 differentiation as defined by IFN-γ production uponsecondary stimulation with anti-CD3 alone. None of the compoundsaffected the viability or recovery of T cells after one week of cultureTABLE 2 EX. CMPD NO. STRUCTURE [IC_(50;) μM] A CT7549

21 B CT11495

35 C CT11499

30 D CT12404

28 E CT12407

30 F CT12422

19 G CT12440

9 H CT12441

19 I CT12447

25 J CT12452

35 K CT12458

27 L CT12459

17 M CT12461

17 N CT12463

31 O CT12464

12 P CT12465

15 Q CT12481

24.7 R CT12485

10 S CT12490

20 T CT17556

23.8 U CT17557

9 V CT22404

10 W CT22464

30 X CT22465

14 Y CT14577

47 Z CT12460

21.8

Example 37 Effect on IFN-γ Production Induced by IL-12

The ability of IL-12 to induce generation of Th1 cells is aided byIFN-γ, a cytokine which is known to be induced by IL-12 itself.(R)-3-(N-biotinyl-6-aminohexyl)-1-(5-hydroxyhexyl)-7-methylxanthine(CT12460) and(R)-3-(N-biotinyl-2-aminoethyl)-1-(5-hydroxyhexyl)-7-methylxanthine(CT13410) were tested in an interferon gamma (IFN-γ) induction assay asdescribed in Kobayashi, M., et al., “Identification and Purification ofNatural Killer Cell Stimulatory Factor (NKSF), A Cytokine with MultipleBiologic Effects on Human Lymphocytes,” J. Exp. Med.U, 170:827-845 (at829, 830 and 836) (1989). See also, Wolf, S., et al., “Interleukin 12: AKey Modulator of Immune Function,” Stem Cells, 12:154-168 (1994) andTrinchieri, supra. FIG. 1 shows that when CT12460 and CT13410 were addedto a culture of a splenocytes, IL-12 induced IFN-γ secretion wasinhibited. Thus, the data shows that CT12460 and CT13410 are botheffective inhibitors of IL-12 signaling in vitro.

Example 38 Metabolic Stability

Compounds of the present invention were shown to be metabolically stableas determined in the microsomal metabolism screening assay generallydescribed below. Compounds of the present invention and(R)-1-(5-Hydroxyhexyl)-3,7-dimethylxanthine (“lisofylline” or “LSF”)(used as a control) were incubated with human or monkey microsomes andthe loss of each was measured and compared.

The incubation solution consisted of 50 uM test compound, human orcynomolgus monkey microsomes and 2 mM nicotine adenine dinucleotidephosphate disodium salt (NADPH) in 100 mM phosphate buffer, pH 7.4.Microsome concentration was adjusted to give approximately 45% loss ofLSF after 60 minutes incubation; average concentrations were 5 mg/mlprotein or 1 mg/ml protein for human or monkey, respectively. Reactioncomponents were placed in loosely capped glass tubes. Incubations werecarried out for 0 and 60 min in an orbital water bath shaker at 37° C.and were stopped by the addition of 1.2 volume methanol. For compoundsthat retain a chiral secondary alcohol, the incubations were stopped bymixing with 6 mL dichloromethane. Incubations were done in duplicate ortriplicate. LSF was incubated in each assay batch as a referencecompound.

In preparation for achiral chromatography, samples were supplementedwith 1-(7-hydroxyheptyl)-3,7-dimethylxanthine (CT1545) (as a standard)to a final concentration of 20 ug/mL and centrifuged at 200 g for 10min. The resultant supernatants were diluted 10 fold with 25 mMpotassium phosphate, pH 3.0. Fifty uL of each sample was chromatographedon a C16 RP Amide column (Supelco), 4.6mm×250mm, 5 micron, at a columntemperature of 35° C. The mobile phase was mixture of 25 mM potassiumphosphate (A) and acetonitrile (B) delivered at 1.0 mL/min as agradient, typically 10% B to 75% B over 15 min. Chromatograms weremonitored at 273 nm or other lambda max.

Incubations stopped with dichloromethane were supplemented with 2.5 μgCT-1545 and frozen. On thawing the organic phase was removed and driedunder a N2 stream, then taken up in 250 μL hexane/isopropanol (90/10).Chromatography was carried out on a Daicel Chiralpak AD column,4.6mm×250mm, 10 micron, held at 35° C. with a 25 μL injection volume andisocratic elution with hexane (+0.2% trichloroacetic acid)/isopropanolat 1.0 ml/min. Mobile phase proportions were adjusted to achievebaseline or near baseline resolution of enantiomers.

Analyte response observed as the ratio of the area of the test compoundpeak or of the LSF peak to the area of the internal standard. The %metabolism was calculated as: (ratio@60 min−ratio@0 min)/ratio@60min×100%. Metabolic stability was expressed as: metabolic index (MI)=%metabolism_(testcompound)/% metabolism LSF.

In this Example, NADPH, monobasic potassium phosphate, dibasic sodiumphosphate and trichloroacetic acid were obtained from Sigma. Organicsolvents were obtained from Burdick and Jackson. Water was distilled anddeionized. Microsomes (In Vitro Technologies) were obtained as frozensuspensions at −70° C. and stored at that temperature until use. Humanmicrosomes represented a pool of 15 individuals representing ca. 50/50gender ratio and monkey microsomes were from a pool of two or moremales. HPLC columns were from Supelco or Daicel. HPLC chromatography wascarried out on Shimadzu series 10 instruments.

Example 39 Adoptive Transfer EAE

An adoptive transfer experimental allergic encephalomyelitis (EAE) modelwas used, in which the splenic T cells from actively immunized mice werecultured for 4 days in antigen-containing (myelin basic protein) medium.The cells were then transferred to naive recipients, which were thenevaluated for clinical changes in motor nerve function in the presenceor absence of treatment with LSE or the compound of Example 22(CT11558). Both compounds were administered on a bid schedule, bygavage, for the first 5 days. FIG. 2 shows that both compounds produceda significant delay in the onset and a decrease in the magnitude ofobservable clinical deficits as compared with animals receivingactivated T cells and gavage with vehicle only.

Example 40 Graft-Versus-Host Disease (GVHD) Model

In a GVHD model, an irradiated F1 hybrid recipient population, bredacross a parental major H2 mismatch, was infused with maternal cellsactivated in vitro with conconavalin A (Con A) and IL-12. LSF and thecompound of Example 7 (CT12441) were compared with a vehicle control forefficacy. Both compounds were administered on a bid schedule, by gavage,for the first 5 days. FIG. 3 shows that both compounds produced asignificant increase of survival, as compared with animals receiving theactivated maternal T cells and gavage with the vehicle control only, asassessed over 36 days after adoptive transfer of cells.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention specifically described herein. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

1. A therapeutic compound, including resolved enantiomers,diastereomers, tautomers, salts and solvates thereof, having thefollowing formula:

wherein: X, Y and Z are independently selected from a member of thegroup consisting of C(R₃), N, N(R₃) and S; R₁ is selected from a memberof the group consisting of hydrogen, methyl, C₍₅₋₉₎alkyl, C₍₅₋₉₎alkenyl,C₍₅₋₉₎alkynyl, C₍₅₋₉₎hydroxyalkyl, C₍₃₋₈₎alkoxyl, C₍₅₋₉₎alkoxyalkyl, theR₁ being optionally substituted; R₂ and R₃ are independently selectedfrom a member of the group consisting of hydrogen, halo, oxo,C₍₁₋₂₀₎alkyl, C₍₁₋₂₀₎hydroxyalkyl, C₍₁₋₂₀₎thioalkyl, C₍₁₋₂₀₎alkylamino,C₍₁₋₂₀₎alkylaminoalkyl, C₍₁₋₂₀₎aminoalkyl, C₍₁₋₂₀₎aminoalkoxyalkenyl,C₍₁₋₂₀₎aminoalkoxyalkynyl, C₍₁₋₂₀₎diaminoalkyl, C₍₁₋₂₀₎triaminoalkyl,C₍₁₋₂₀₎tetraaminoalkyl, C₍₅₋₁₅₎aminotrialkoxyamino, C₍₁₋₂₀₎alkylamido,C₍₁₋₂₀₎alkylamidoalkyl, C₍₁₋₂₀₎amidoalkyl, C₍₁₋₂₀₎acetamidoalkyl,C₍₁₋₂₀₎alkenyl, C₍₁₋₂₀₎alkynyl, C₍₃₋₈₎alkoxyl, C₍₁₋₁₁₎alkoxyalkyl, andC₍₁₋₂₀₎dialkoxyalkyl; with the proviso that R₁ is not an ω-1 secondaryalcohol substituted C₍₅₋₈₎ alkyl when both X and Y are N(R₃), Z is C(R₃)and R₃ is H or C₍₁₋₃₎ alkyl.
 2. The therapeutic compound of claim 1,wherein R₁ is substituted with a member of the group consisting of N—OH,acylamino, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl(mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino,phosphinyl, phospho, phosphono and —NR^(a)R^(b), wherein each of R^(a)and R^(b) may be the same or different and each is selected from thegroup consisting of hydrogen, optionally substituted alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic group.3. The therapeutic compound of claim 1, wherein R₂ and R₃ are selectedfrom the group consisting of methyl, ethyl, oxo, isopropyl, n-propyl,isobutyl, n-butyl, t-butyl, 2-hydroxyethyl, 3-hydroxypropyl,3-hydroxy-n-butyl, 2methoxyethyl, 4-methoxy-n-butyl, 5-hydroxyhexyl,2-bromopropyl, 3-dimethylaminobutyl, 4-chloropentyl, methylamino,aminomethyl, and methylphenyl.
 4. The therapeutic compound of claim 1,wherein each R₂ and R₃ is substituted with one or more members of thegroup consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl,biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group,cyano group, sulfo, sulfonyl, sulfinyl., sulfhydryl, sulfeno,sulfanilyl, sulfamyl, sulfamino, phosphino, phosphinyl, phospho,phosphono, N—OH, —Si(CH₃)₃, C₍₁₋₃₎alkyl, C₍₁₋₃₎hydroxyalkyl,C₍₁₋₃₎thioalkyl, C₍₁₋₃₎alkylamino, benzyldihydrocinnamoyl group,benzoyldihydrocinnamido group, optionally substituted heterocyclic groupand optionally substituted carbocyclic group.
 5. The therapeuticcompound of claim 4, wherein the heterocyclic group or carbocyclic groupis substituted with one or more members of the group consisting of halo,hydroxyl, nitro, SO₂NH₂, C₍₁₋₆₎alkyl, C₍₁₋₆₎haloalkyl, C₍₁₋₈₎alkoxyl,C₍₁₋₁₁₎alkoxyalkyl, C₍₁₋₆₎alkylamino, and C₍₁₋₆₎aminoalkyl.
 6. Thetherapeutic compound of claim 4, wherein the heterocyclic group is amember selected from the group consisting of acridinyl, aziridinyl,azocinyl, azepinyl, benzimidazolyl, benzodioxolanyl, benzofuranyl,benzothiophenyl, carbazole, 4a H-carbazole, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, dioxoindolyl, furazanyl, furyl,furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthalenyl, naphthyridinyl, norbornanyl,norpinanyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, oxiranyl,perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenyl,phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, piperidyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazoliny),pyrazolyl, pyrenyl, pyridazinyl, pyridinyl, pyridyl, pyridyl,pyrimidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolonyl, pyrrolyl,2H-pyrrolyl, quinazolinyl, 4H-quinolizinyl, quinolinyl, quinoxalinyl,quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,2H-,6H-1,5,2-dithiazinyl, thianthrenyl, thiazolyl, thienyl, thiophenyl,triazinyl, xanthenyl and xanthinyl.
 7. The therapeutic compound of claim4, wherein the carbocyclic group is a member selected from the groupconsisting of adamantyl, anthracenyl, benzamidyl, benzyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hexanyl, bicyclo[2.2.2]octanyl,bicyclo[3.2.0]heptanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl,biphenyl, biscyclooctyl, cyclobutyl, cyclobutenyl, cycloheptyl,cycloheptenyl, cyclohexanedionyl, cyclohexenyl, cyclohexyl,cyclooctanyl, cyclopentadienyl, cyclopentanedionyl, cyclopentenyl,cyclopentyl, cyclopropyl, decalinyl, 1,2-diphenylethanyl, indanyl,1-indanonyl, indenyl, naphthyl, napthlalenyl, phenyl, resorcinolyl,stilbenyl, tetrahydronaphthyl, tetralinyl, tetralonyl, andtricyclododecanyl.
 8. A compound having the formula

or a pharmaceutically acceptable salt thereof.
 9. A compound having theformula

or a pharmaceutically acceptable salt thereof.
 10. A compound having theformula

or a pharmaceutically acceptable salt thereof.
 11. A compound having theformula

12-15. (CANCELED)
 16. A compound, or pharmaceutically acceptable satthereof, selected from the group consisting of:


17. A compound, or pharmaceutically acceptable salt thereof, selectedfrom the group consisting of the compounds defined in Table
 1. 18. Apharmaceutical composition comprising the compound of claim 1 inadmixture with a pharmaceutically acceptable carrier, adjuvant orvehicle.
 19. A method for inhibiting a cellular process or activitymediated by IL-12, the method comprising: (a) contacting L12 responsivecells with a compound as defined in claim 1; and (b) determining thatthe cellular process or activity mediated by IL-12 is inhibited.
 20. Themethod of claim 19, wherein step (a) is carried out in vitro.
 21. Themethod of claim 19, wherein said cellular process is the differentiationof naive T cells into Th1 cells.
 22. The method of claim 19, whereinsaid activity is the secretion of proinflammatory cytokines.
 23. Themethod of claim 22, wherein said cytokines are secreted by Th1 cells.24. A method for treating a Th1 cell-mediated inflammatory response in amammal in need of such treatment, the method comprising: administeringto the mammal a therapeutically effective amount of the compound definedin claim 1, wherein said compound is capable of inhibiting an IL-12mediated cellular process or activity, thereby inhibiting theinflammatory response.
 25. The method of claim 24, wherein theinflammatory response is associated with a disease or condition selectedfrom the group consisting of chronic inflammatory disease, chronicintestinal inflammation, arthritis, psoriasis, asthma and autoimmunedisorders.
 26. The method of claim 25, wherein the inflammatory responseis associated with an autoimmune disorder.
 27. The method of claim 26,wherein said autoimmune disorder is selected from type-1 IDDM, multiplesclerosis, rheumatoid arthritis, uveitis, inflammatory bowel disease,lupus disorders, and acute and chronic graft-versus-host disease. 28.The method of claim 24, wherein said mammal is a human.
 29. Atherapeutic compound, including resolved enantiomers, diastereomers,tautomers, salts and solvates thereof, having the following formula:

wherein: X, Y and Z are independently selected from a member of thegroup consisting of C(R₃), N, N(R₃) and S; R₁ is selected from a memberof the group consisting of hydrogen, methyl, substituted alkyl,C₍₅₋₉₎alkenyl, C₍₅₋₉₎alkynyl, C₍₅₋₉₎hydroxyalkyl, C₍₃₋₈₎alkoxyl,C₍₅₋₉₎alkoxyalkyl, the R₁ being optionally substituted; R₂ and R₃ areindependently selected from a member of the group consisting ofhydrogen, halo, oxo, C₍₁₋₂₀₎alkyl, C₍₁₋₂₀₎hydroxyalkyl,C₍₁₋₂₀₎thioalkyl, C₍₁₋₂₀₎alkylamino, C₍₁₋₂₀₎alkylaminoalkyl,C₍₁₋₂₀₎aminoalkyl, C₍₁₋₂₀₎aminoalkoxyalkenyl, C₍₁₋₂₀₎aminoalkoxyalkynyl,C₍₁₋₂₀₎diaminoalkyl, C₍₁₋₂₀₎triaminoalkyl, C₍₁₋₂₀₎tetraaminoalkyl,C₍₅₋₁₅₎aminotrialkoxyamino, C₍₁₋₂₀₎alkylamido, C₍₁₋₂₀₎alkylamidoalkyl,C₍₁₋₂₀₎amidoalkyl, C₍₁₋₂₀₎acetamidoalkyl, C₍₁₋₂₀₎alkenyl,C₍₁₋₂₀₎alkynyl, C₍₃₋₈₎alkoxyl, C₍₁₋₁₁₎alkoxyalkyl, andC₍₁₋₂₀₎dialkoxyalkyl; with the proviso that R₁ is not an ω-1 secondaryalcohol substituted C₍₅₋₈₎ alkyl when both X and Y are N(R₃), Z is C(R₃)and R₃ is H or C₍₁₋₃₎ alkyl.
 30. The therapeutic compound of claim 29,wherein R₁ is substituted with a member of the group consisting of N—OH,acylamino, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl(mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino,phosphinyl, phospho, phosphono and —NR^(a)N^(b), wherein each of R^(a)and R^(b) may be the same or different and each is selected from thegroup consisting of hydrogen, optionally substituted alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic group.31. The therapeutic compound of claim 29, wherein R₂ and R₃ are selectedfrom the group consisting of methyl, ethyl, oxo, isopropyl, n-propyl,isobutyl, n-butyl, t-butyl, 2-hydroxyethyl, 3-hydroxypropyl,3-hydroxy-n-butyl, 2methoxyethyl, 4-methoxy-n-butyl, 5-hydroxyhexyl,2-bromopropyl, 3-dimethylaminobutyl, 4-chloropentyl, methylamino,aminomethyl, and methylphenyl.
 32. The therapeutic compound of claim 29,wherein each R₂ and R₃ is substituted with one or more members of thegroup consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl,biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group,cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl, sulfeno, sulfanilyl,sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono, N—OH,—Si(CH₃)₃, C₍₁₋₃₎alkyl, C₍₁₋₃₎hydroxyalkyl, C₍₁₋₃₎thioalkyl,C₍₁₋₃₎alkylamino, benzyldihydrocinnamoyl group, benzoyldihydrocinnamidogroup, optionally substituted heterocyclic group and optionallysubstituted carbocyclic group.
 33. The therapeutic compound of claim 32,wherein the heterocyclic group or carbocyclic group is substituted withone or more members of the group consisting of halo, hydroxyl, nitro,SO₂NH₂, C₍₁₋₆₎alkyl, C₍₁₋₆₎haloalkyl, C₍₁₋₈₎alkoxyl, C₍₁₋₁₁₎alkoxyalkyl,C₍₁₋₆₎alkylamino, and C₍₁₋₆₎aminoalkyl.
 34. The therapeutic compound ofclaim 32, wherein the heterocyclic group is a member selected from thegroup consisting of acridinyl, aziridinyl, azocinyl, azepinyl,benzimidazolyl, benzodioxolanyl, benzofuranyl, benzothiophenyl,carbazole, 4a H-carbazole, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, dioxoindolyl, furazanyl, furyl, furfuryl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthalenyl, naphthyridinyl, norbornanyl,norpinanyl, octahydroisoquinolinyl, oxazolidinyl, oxazolyl, oxiranyl,perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phenyl,phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, piperidyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyrenyl, pyridazinyl, pyridinyl, pyridyl, pyridyl,pyrimidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolonyl, pyrrolyl,2H-pyrrolyl, quinazolinyl, 4H-quinolizinyl, quinolinyl, quinoxalinyl,quinuclidinyl, B-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,2H-,6H-1,5,2-dithiazinyl, thianthrenyl, thiazolyl, thienyl, thiophenyl,triazinyl, xanthenyl and xanthinyl.
 35. The therapeutic compound ofclaim 32, wherein the carbocyclic group is a member selected from thegroup consisting of adamantyl, anthracenyl, benzamidyl, benzyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hexanyl, bicyclo[2.2.2]octanyl,bicyclo[3.2.0]heptanyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decanyl,biphenyl, biscyclooctyl, cyclobutyl, cyclobutenyl, cycloheptyl,cycloheptenyl, cyclohexanedionyl, cyclohexenyl, cyclohexyl,cyclooctanyl, cyclopentadienyl, cyclopentanedionyl, cyclopentenyl,cyclopentyl, cyclopropyl, decalinyl, 1,2-diphenylethanyl, indanyl,1-indanonyl, indenyl, naphthyl, napthlalenyl, phenyl, resorcinolyl,stilbenyl, tetrahydronaphthyl, tetralinyl, tetralonyl, andtricyclododecanyl.
 36. A pharmaceutical composition comprising thecompound of claim 29 in admixture with a pharmaceutically acceptablecarrier, adjuvant or vehicle.
 37. A method for inhibiting a cellularprocess or activity mediated by IL-12, the method comprising: (a)contacting, IL-12 responsive cells with a compound as defined in claim29; and (b) determining that the cellular process or activity mediatedby IL-12 is inhibited.
 38. The method of claim 37, wherein step (a) iscarried out in vitro.
 39. The method of claim 37, wherein said cellularprocess is the differentiation of naive T cells into Th1 cells.
 40. Themethod of claim 37, wherein said activity is the secretion ofproinflammatory cytokines.
 41. The method of claim 40, wherein saidcytokines are secreted by Th1 cells.
 42. A method for treating a Th1cell-mediated inflammatory response in a mammal in need of suchtreatment, the method comprising: administering to the mammal atherapeutically effective amount of the compound defined in claim 29,wherein said compound is capable of inhibiting an EL-12 mediatedcellular process or activity, thereby inhibiting the inflammatoryresponse.
 43. The method of claim 42, wherein the inflammatory responseis associated with a disease or condition selected from the groupconsisting of chronic inflammatory disease, chronic intestinalinflammation, arthritis, psoriasis, asthma and autoimmune disorders. 44.The method of claim 43, wherein the inflammatory response is associatedwith an autoimmune disorder.
 45. The method of claim 44, wherein saidautoimmune disorder is selected from type-1 IDDM, multiple sclerosis,rheumatoid arthritis, uveitis, inflammatory bowel disease, lupusdisorders, and acute and chronic graft-versus-host disease.
 46. Themethod of claim 42, wherein said mammal is a human.